CN107709334A - New amino acid derivativges, its preparation method and include their Pharmaceutical composition - Google Patents
New amino acid derivativges, its preparation method and include their Pharmaceutical composition Download PDFInfo
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- CN107709334A CN107709334A CN201680039612.9A CN201680039612A CN107709334A CN 107709334 A CN107709334 A CN 107709334A CN 201680039612 A CN201680039612 A CN 201680039612A CN 107709334 A CN107709334 A CN 107709334A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The present invention discloses formula (I) compound, in formula (I), R1、R2、R5、R6、R7、R12, X, Y, A, E and n be defined as in the description.Invention additionally discloses medicine.
Description
The present invention relates to new amino acid derivativges, its preparation method and include their Pharmaceutical composition.
The compounds of this invention is noval chemical compound, has very valuable pharmacology special in Apoptosis and cancer field
Property.
Apoptosis or apoptosis are to maintain have most important effect to embryonic development and tissue homeostasis
Physiology course.
Apoptosis type cell death is related to morphological change (such as karyopyknosis, DNA fragmentation) and biochemistry shows
As (such as activation of cysteine proteinase), it can result in the damage of cell key constituent, induce it to disintegrate and dead
Die.The regulation of apoptosis process is complexity and is related to activation or the suppression (Cory of signal transduction pathway in various kinds of cell
S. etc., Nature Review Cancer 2002,2,647-656).
The imbalance of apoptosis is related to some pathology.The increase of Apoptosis is relevant with nerve degenerative diseases, such as pa gold
Gloomy disease, Alzheimer's and ischaemic.On the contrary, the defects of Apoptosis carry out process is in cancer and its chemoresistance
Development, autoimmune disease, inflammatory disease and virus infection in play an important role.Therefore, the shortage of Apoptosis is cancer
One of phenotypic characteristic of disease (Hanahan D. etc., Cell 2000,100,57-70).
The anti-apoptotic proteins of Bcl-2 families are relevant with many pathology.In the cancer Zhong Junyou Bcl-2 families of many types
The description participated of protein, such as colon cancer, breast cancer, ED-SCLC, non-small cell lung cancer, carcinoma of urinary bladder, ovary
Cancer, prostate cancer, chronic lymphocytic leukemia, lymthoma, myeloma, acute myeloblastic leukemia, cancer of pancreas etc..Bcl-2
The overexpression of family's anti-apoptotic proteins is related to tumour and occurred, to the resistance of chemotherapy and the clinical prognosis of cancer patient.It is worth
It is noted that anti-apoptotic Bcl-2 family members Mcl-1 have in various cancers overexpression (Beroukhim R. etc.,
Nature 2010,899-905).Therefore, it is required to suppress the anti-apoptotic activities of the protein of Bcl-2 families in the treatment
Compound.
In addition to being noval chemical compound, the compounds of this invention, which has, promotees apoptosis properties, makes it can be used for withering with cell
Die in the relevant pathology of defect, such as treating cancer and immune and autoimmune disease.
More particularly it relates to formula (I) compound：
Wherein：
◆ A is represented
Wherein 1 is connected with-NH- groups, and 2 are connected with aromatic ring,
◆ E representation ring alkyls, Heterocyclylalkyl, aryl or heteroaryl,
◆ X represents nitrogen-atoms or C-R4Group,
◆ Y represents nitrogen-atoms or C-R3Group,
◆R1Represent halogen atom, straight or branched (C1-C6) alkyl, straight or branched (C2-C6) alkenyl, straight chain or branch
Chain (C2-C6) alkynyl, straight or branched (C1-C6) multi-haloalkyl, hydroxyl, hydroxyl (C1-C6) alkyl, straight or branched (C1-C6)
Alkoxy ,-S- (C1-C6) alkyl, cyano group, nitro ,-alkyl (C0-C6)-NR9R9' ,-O- alkyl (C1-C6)-NR9R9' ,-O- alkane
Base (C1-C6)-R10、-C(O)-OR9、-O-C(O)-R9、-C(O)-NR9R9’、-NR9-C(O)-R9’、-NR9-C(O)-OR9' ,-alkane
Base (C1-C6)-NR9-C(O)-R9’、-SO2-NR9R9’、-SO2- alkyl (C1-C6),
◆R2、R3、R4And R5It is independent each other to represent hydrogen atom, halogen atom, straight or branched (C1-C6) alkyl, straight
Chain or side chain (C2-C6) alkenyl, straight or branched (C2-C6) alkynyl, straight or branched (C1-C6) multi-haloalkyl, hydroxyl, hydroxyl
Base (C1-C6) alkyl, straight or branched (C1-C6) alkoxy ,-S- (C1-C6) alkyl, cyano group, nitro ,-alkyl (C0-C6)-
NR9R9' ,-O- alkyl (C1-C6)-NR9R9' ,-O- alkyl (C1-C6)-R10、-C(O)-OR9、-O-C(O)-R9、-C(O)-
NR9R9’、-NR9-C(O)-R9’、-NR9-C(O)-OR9' ,-alkyl (C1-C6)-NR9-C(O)-R9’、-SO2-NR9R9' or-SO2- alkane
Base (C1-C6), or a pair of (R1,R2) substituent the virtue of 5-7 ring members composition is formed together with the carbon atom for carrying them
Race or non-aromatic ring, it can contain the hetero atoms that 1-3 is selected from oxygen, sulphur and nitrogen, it will be appreciated that the ring formed can be by
1-2 substitute selected from following group：Halogen, straight or branched (C1-C6) alkyl ,-alkyl (C0-C6)-NR9R9’、-
NR11R11' ,-alkyl (C0-C6)-Cy1Or oxo,
◆R6Represent hydrogen atom, halogen atom, straight or branched (C1-C6) alkyl, straight or branched (C2-C6) alkenyl,
Straight or branched (C2-C6) alkynyl, straight or branched (C1-C6) multi-haloalkyl, hydroxyl, straight or branched (C1-C6) alcoxyl
Base ,-S- (C1-C6) alkyl, cyano group, nitro ,-alkyl (C0-C6)-NR9R9’、-O-Cy1,-alkyl (C0-C6)-Cy1,-alkenyl
(C2-C6)-Cy1,-alkynyl (C2-C6)-Cy1,-O- alkyl (C1-C6)-R10、-C(O)-OR9、-O-C(O)-R9、-C(O)-
NR9R9’、-NR9-C(O)-R9’、-NR9-C(O)-OR9' ,-alkyl (C1-C6)-NR9-C(O)-R9’、-SO2-NR9R9' or-SO2- alkane
Base (C1-C6),
◆R7Represent hydrogen atom, straight or branched (C1-C8) alkyl ,-CHRaRb, aryl, heteroaryl, aryl alkyl (C1-
C6) or heteroaryl alkyl (C1-C6),
◆R8Represent straight or branched (C1-C6) alkyl, straight or branched (C2-C6) alkenyl, straight or branched (C2-C6)
Alkynyl ,-Cy2, halogen atom, cyano group ,-C (O)-R11Or-C (O)-NR11R11',
◆R9And R9' hydrogen atom, straight or branched (C are independently represented each other1-C6) alkyl, or a pair of (R9、R9')
Aromatics or the non-aromatic ring that 5-7 ring memberses form are formed together with substituent and the nitrogen-atoms for carrying them, it is except nitrogen-atoms
The 1-3 hetero atoms for being selected from oxygen, sulphur and nitrogen can be contained outside, it will be appreciated that the nitrogen can represent hydrogen atom or straight by one
Chain or side chain (C1-C6) alkyl group substitution,
◆R10Representative-Cy3、-Cy3- alkyl (C0-C6)-Cy4、-C(O)-NR9R9’、-NR9R9’、-OR9、-NR9-C(O)-
R9' ,-O- alkyl (C1-C6)-OR9、-SO2-R9、-C(O)-OR9Or-NH-C (O)-NH-R9,
◆R11And R11' hydrogen atom or optionally substituted straight or branched (C are independently represented each other1-C6) alkyl,
◆R12Represent hydrogen atom, hydroxyl or hydroxyl (C1-C6) alkyl,
◆RaRepresent hydrogen atom or straight or branched (C1-C6) alkyl,
◆RbRepresentative-O-C (O)-O-Rc、-O-C(O)-NRcRc' or-O-P (O) (ORc)2,
◆RcAnd Rc' hydrogen atom, straight or branched (C are independently represented each other1-C8) alkyl, cycloalkyl, (C1-C6) alkane
Epoxide (C1-C6) alkyl, (C1-C6) alkoxy carbonyl (C1-C6) alkyl, or a pair of (Rc,Rc') substituent and carry theirs
Nitrogen-atoms forms the non-aromatic ring of 5-7 ring members composition together, its can contain except nitrogen-atoms in addition to 1-3 selected from oxygen with
The hetero atom of nitrogen, it will be appreciated that the nitrogen can be expressed straight or branched (C1-C6) alkyl a group substitution,
◆Cy1、Cy2、Cy3And Cy4It is independent each other to represent cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl,
◆ n is the integer equal to 0,1 or 2,
It should be understood that：
- " aryl " refers to phenyl, naphthyl, xenyl,
- " heteroaryl " refers to any single- or double- cyclic group being made up of 5-10 ring memberses, and it has at least one
Aromatic fractions and the hetero atoms selected from oxygen, sulphur and nitrogen containing 1-3,
- " cycloalkyl " refers to any single- or double- cyclic non-aromatic carbon ring group, and it contains 3-10 ring memberses,
- " Heterocyclylalkyl " refers to any single- or double- cyclic non-aromatic carbon ring group, and it contains 3-10 ring memberses and contained
There are the 1-3 hetero atoms for being selected from oxygen, sulphur and nitrogen, it can include fusion, bridging or spirocyclic ring system,
So defined aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl and alkyl, alkenyl, alkynyl, alkoxy may
Substituted by 1-4 selected from following group：Straight or branched (the C optionally substituted1-C6) alkyl, the straight chain that optionally substitutes or branch
Chain (C2-C6) alkenyl, the straight or branched (C that optionally substitutes2-C6) alkynyl, the straight or branched (C that optionally substitutes1-C6) alcoxyl
The base, (C optionally substituted1-C6) alkyl-S-, hydroxyl, hydroxyl (C1-C6) alkyl, oxo (or N- oxides, if appropriate
Words), nitro, cyano group ,-C (O)-OR ' ,-O-C (O)-R ' ,-C (O)-NR ' R " ,-O-C (O)-NR ' R " ,-NR ' R " ,-(C=
NR’)-OR”、-O-P(O)(OR’)2、-O-P(O)(O-M+)2, straight or branched (C1-C6) multi-haloalkyl, trifluoromethoxy, halogen
The aldohexose of element or following formula：
Wherein each R ' is independent；
It should be appreciated that the R ' and R " is independent each other to represent hydrogen atom or optionally substituted straight or branched (C1-
C6) alkyl, M+Pharmaceutically useful univalent cation is represented,
Their enantiomer, diastereoisomer and atropisomer and its addition formed with pharmaceutically useful acid or alkali
Salt.
It is preferred that the present invention relates to formula (I) compound, wherein：
◆R1And R2It is independent each other to represent halogen atom, straight or branched (C1-C6) alkyl, hydroxyl, hydroxyl (C1-C6)
Alkyl, straight or branched (C1-C6) alkoxy,
Or a pair of (R1,R2) substituent form the virtue being made up of 5-7 ring memberses together with the carbon atom for carrying them
Race's ring, it can include 1-3 nitrogen-atoms, it will be appreciated that the ring formed can be taken by 1-2 selected from following group
Generation：Halogen, straight or branched (C1-C6) alkyl or-alkyl (C0-C6)-NR9R9',
◆R3Represent hydrogen atom, halogen atom, straight or branched (C1-C6) alkyl, hydroxyl, straight or branched (C1-C6) alkane
Epoxide or-O- alkyl (C1-C6)-NR9R9',
◆R4And R5It is independent each other to represent hydrogen atom, halogen atom, straight or branched (C1-C6) alkyl, hydroxyl, straight
Chain or side chain (C1-C6) alkoxy,
◆R6Represent hydrogen atom, halogen atom, straight or branched (C1-C6) alkyl, straight or branched (C1-C6) alkyl polyhalides
Base, hydroxyl, straight or branched (C1-C6) alkoxy, cyano group, nitro ,-alkyl (C0-C6)-NR9R9' ,-alkyl (C0-C6)-Cy1、-
O- alkyl (C1-C6)-R10Or-C (O)-NR9R9’,
◆R7Represent hydrogen atom, straight or branched (C1-C8) alkyl ,-CHRaRbOr heteroaryl alkyl (C1-C6),
◆R8Represent straight or branched (C1-C6) alkyl, straight or branched (C2-C6) alkenyl, straight or branched (C2-C6)
Alkynyl ,-Cy2, halogen atom or-C (O)-R11,
◆R9And R9' hydrogen atom, straight or branched (C are independently represented each other1-C6) alkyl, or a pair of (R9,R9')
The non-aromatic ring of 5-7 ring members composition is formed together with substituent and the nitrogen-atoms for carrying them, it can be with addition to nitrogen-atoms
The hetero atom selected from oxygen and nitrogen containing 1-3, it will be appreciated that the nitrogen can be expressed straight or branched (C1-C6) alkyl
One group substitution,
◆R10Representative-Cy3Or-Cy3- alkyl (C0-C6)-Cy4,
◆R11Represent straight or branched (C1-C6) alkyl,
So defined aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl and alkyl, alkenyl, alkynyl, alkoxy can be with
Substituted by 1-4 selected from following group：Straight or branched (the C optionally substituted1-C6) alkyl, the straight chain that optionally substitutes or branch
Chain (C1-C6) alkoxy, hydroxyl, hydroxyl (C1-C6) alkyl, oxo (or N- oxides, if appropriate) ,-C (O)-OR ' ,-
C(O)-NR’R”、-O-C(O)-NR’R”、-NR’R”、-O-P(O)(OR’)2、-O-P(O)(O-M+)2, straight or branched (C1-C6)
The aldohexose of multi-haloalkyl, halogen or following formula：
Wherein each R ' is independent；
It should be appreciated that the R ' and R " is independent each other to represent hydrogen atom or optionally substituted straight or branched (C1-
C6) alkyl, M+Represent pharmaceutically useful univalent cation.
It is pharmaceutically useful acid in, it can be mentioned that but be not added with any restriction be hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid,
Trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, butanedioic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, Vitamin C
Acid, oxalic acid, Loprazolam, camphoric acid etc..
In pharmaceutically useful alkali, it can be mentioned that but be not added with any restriction is sodium hydroxide, potassium hydroxide, triethylamine, tert-
Butylamine etc..
More particularly, preferable formula (I) compound is the compound that wherein n is the integer equal to 1.
In another embodiment of the present invention, beneficial possibility by formula (I-a) compound group into：
Wherein A, E, R1、R2、R5、R6、R7、R12, X, Y and n such as formula (I) defined.
Atropisomer is caused stereoisomer due to singly-bound blocked rotation, due to steric strain or other participations
Capacity volume variance cause spinning obstacle, the obstacle is sufficiently high to be made it possible to separate single rotamer.Change for the present invention
Compound, atropisomer are as follows：
When X represents C-R4Group and Y represents C-R3During group, preferable atropisomer is (5Sa)。
It is advantageous that it is selected from R2、R3、R4And R5Group at least one group do not indicate that hydrogen atom.
It is preferred that R12Represent hydrogen atom, hydroxymethyl or hydroxyethyl.More preferably R12Represent hydrogen atom.
In currently preferred compound, R1Represent straight or branched (C1-C6) alkyl or halogen atom.It is further preferred that R1
Represent methyl, ethyl, bromine atoms or chlorine atom.Even more preferably, R1Represent methyl.
It is advantageous that R2Represent halogen atom, hydroxyl, straight or branched (C1-C6) alkoxy.It is further preferred that R2Represent methoxy
Base, hydroxyl, fluorine atom, bromine atoms or chlorine atom.Even more preferably, R2Represent chlorine atom.
In some preferred embodiments of the present invention, as a pair of (R1,R2) substituent and carry their carbon atom
When forming aromatic ring together,
Represent
Wherein R13Represent hydrogen atom, straight or branched (C1-C6) alkyl or-alkyl (C0-C6)-NR9R9', wherein R9And R9’
As formula (I) defines, R14Represent hydrogen atom, halogen atom or straight or branched (C1-C6) alkyl.
R13It is preferred that represent hydrogen atom, methyl or-(CH2)m-NR9R9', wherein m be 2 or 3 integer, R9And R9' represent first
Base, or a pair of (R9,R9') substituent with carry their nitrogen-atoms together with formed pyrrolidinyl, piperidyl, morpholinyl or
4- thyl-piperazin -1- bases.
R14Advantageously represent hydrogen atom, bromine atoms, iodine atom, chlorine atom or methyl.R14It is preferred that in the β positions quilt of nitrogen-atoms
Substitution.
It is preferred that X represents C-R4Group.In a preferred embodiment of the invention, Y represents C-R3Group.R3Advantageously represent
Hydrogen atom, straight or branched (C1-C6) alkoxy or-O- alkyl (C1-C6)-NR9R9’。R4It is preferred that represent hydrogen atom.
In the certain preferred embodiments of the present invention,
RepresentWherein R1、R2、R9And R9' such as formula
(I) defined.
In currently preferred compound,
Represent
Wherein R9And R9' define such as formula (I).
R5It is preferred that represent hydrogen atom.
In an advantageous embodiment, a pair of (R1,R5) substituent be identical, a pair of (R2,R4) substituent
And identical.In currently preferred compound, a pair of (R1,R5) substituent be identical, represent (C1-C6) alkyl,
It is preferred that methyl, while a pair of (R2,R4) substituent be identical, represent halogen atom, preferably chlorine atom or hydrogen atom.
In another embodiment of the present invention, E represents phenyl, pyridine -2- bases, cyclohexyl, pyrazol-1-yl, ring penta
Base, indoles -4- bases, cyclopropyl, pyridin-3-yl, indol-3-yl, naphthalene -1- bases, imidazol-4 yl or pyridin-4-yl.Advantageously
It is that E represents phenyl.
In currently preferred compound, R6Represent hydrogen atom；Fluorine atom；Chlorine atom；Bromine atoms；Methyl；Fluoroform
Base；Hydroxyl；Methoxyl group；Linear (the C being substituted with halogen atoms1-C6) alkoxy ,-C (O)-NR ' R " groups or-NR ' R " groups；
Cyano group；Nitro；Amino methyl；Benzyl；- O- alkyl (C1-C6)-R10；-C(O)-NR9R9’.It is preferred that R6Representation methoxy, 2,2,
2- trifluoro ethoxies or-O- alkyl (C1-C6)-R10。
In another embodiment of the present invention, favourable possibility by formula (I-b) compound group into：
Wherein R1、R2、R5、R6、R7、R12, X, Y, A and n such as formula (I) defined.
In another embodiment of the present invention, favourable possibility by formula (I-c) compound group into：
Wherein R6、R7、R9、R9’、R12Defined with A such as formulas (I).
It is preferred that R7Represent hydrogen atom ,-CHRaRbGroup, optionally substituted straight or branched (C1-C8) alkyl or heteroaryl
Alkyl (C1-C6) group.It is preferred that R7Representative-CHRaRbGroup, wherein RaRepresent hydrogen atom or methyl, RbRepresentative-O-C (O)-O-
(C1-C8) alkyl；- O-C (O)-O-ring alkyl；-O-C(O)-NRcRc' group, wherein RcAnd Rc' hydrogen original is independently represented each other
Son, straight or branched (C1-C8) alkyl, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy carbonyl (C1-C6) alkyl,
Or a pair of (Rc,Rc') substituent the non-aromatic ring of 5-7 ring members composition is formed together with the nitrogen-atoms for carrying them,
It can include the 1-3 hetero atoms selected from oxygen and nitrogen in addition to nitrogen-atoms；Or-O-P (O) (OH)2Group.Preferable R7Group
It is as follows：Hydrogen；Methyl；Ethyl；(5- methyl -2- oxo -1,3- dioxole -4- bases) methyl；-CHRaRbGroup, wherein
RaRepresent methyl, RbRepresentative-O-C (O)-O-CH2CH3Group or-O-C (O)-N (CH3)2Group.Even more preferably, R7Represent hydrogen.
In currently preferred compound, R8Represent straight or branched (C2-C6) alkynyl, aryl or heteroaryl.It is more excellent
Choosing, R8Represent propyl- 1- alkynes -1- bases, phenyl or furans -2- bases.In a more preferred embodiment, R8Represent propyl- 1- alkynes -1- bases,
4- fluorophenyls or 5- fluorine furans -2- bases.Even more preferably, R8Represent 4- fluorophenyls.
In currently preferred compound, R9And R9' straight or branched (C is independently represented each other1-C6) alkyl, or
A pair of (R of person9,R9') substituent the non-aromatic ring of 5-7 ring members composition is formed together with the nitrogen-atoms for carrying them, its
The 1-3 hetero atoms selected from oxygen and nitrogen can be contained in addition to nitrogen-atoms, it will be appreciated that the nitrogen can be by straight or branched
(C1-C6) alkyl substitution.It is further preferred that R9And R9' represent methyl, or a pair of (R9,R9') substituent formed together 4- methyl-
Piperazinyl.
It is advantageous that R10Representative-Cy3Or-Cy3- alkyl (C0-C6)-Cy4.It is preferred that R10Representative-Cy3Or-Cy3-Cy4。
Cy3It is preferred that representation ring alkyl, particularly cyclopenta.In a preferred embodiment, Cy3Aryl is represented, especially
It is phenyl.It is advantageous that Cy3Represent heteroaryl, particularly pyrimidine radicals, pyrazolyl or pyridine radicals.It is further preferred that Cy3Represent pyrimidine-
4- bases, pyrazoles -5- bases or pyridine -2- bases.In currently preferred compound, Cy3Represent pyrimidine-4-yl.The present invention's
In another embodiment, Cy3Heteroaryl is represented, it can be substituted by following groups：Optionally substituted straight or branched (C1-
C6) alkyl, optionally substituted straight or branched (C1-C6) alkoxy or straight or branched (C1-C6) multi-haloalkyl.It is preferred that
Cy3Heteroaryl is represented, it can be substituted by following groups：2,2,2- trifluoro ethoxies, 2- methoxy ethyls, ethyoxyl；Tert- fourth
Base, ethyl, n-butyl, 2,2,2- trifluoroethyls or methyl.
Cy4It is preferred that represent phenyl, pyridine radicals, pyridazinyl, pyrazinyl, pyrimidine radicals or morpholinyl.It is further preferred that Cy4Represent benzene
Base.
Preferable other the compounds of this invention are following compounds, wherein：
R10Represent
Wherein p be 0 or 1 integer, R15Represent hydrogen atom, hydroxyl, optionally substituted straight or branched (C1-C6) alkane
Base, straight or branched (C1-C6) alkoxy ,-O- (CHR16-CHR17-O)q- R ' group ,-O-P (O) (OR ')2Group ,-O-P (O)
(O-M+)2Group ,-O-C (O)-NR18R19Group, two (C1-C6) alkyl amino (C1-C6) alkoxy, halogen atom or following formula oneself
Aldose：
Wherein each R ' is independent；
It should be understood that：
◆ R ' represents hydrogen atom or straight or branched (C1-C6) alkyl,
◆R16Represent hydrogen atom or (C1-C6) alkoxy (C1-C6) alkyl,
◆R17Represent hydrogen atom or hydroxyl (C1-C6) alkyl,
◆R18Represent hydrogen atom or (C1-C6) alkoxy (C1-C6) alkyl,
◆R19Represent (C1-C6) alkoxy (C1-C6) alkyl ,-(CH2)r-NR9R9' group or-(CH2)r-O-(CHR16-
CHR17-O)q- R ' group,
◆ q 1,2 or 3 integer, r are 0 or 1 integer,
◆M+Represent pharmaceutically useful univalent cation.
The aldohexose of the present invention is preferably D-MANNOSE.It is advantageous that R15Representation methoxy, 2- methoxy ethoxies or
Fluorine.It is preferred that group-(CH2)p-R15Positioned at the ortho position of phenyl.
In preferable the compounds of this invention, it can be mentioned that include：
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorophenyls)
Thieno [2,3-d] pyrimidine-4-yl] -2- [(1- methyl isophthalic acid H- pyrazoles -5- bases) methoxyl group]-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorophenyls)
Thieno [2,3-d] pyrimidine-4-yl] -2- [(2- ethyoxyls pyrimidine-4-yl) methoxyl group]-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorophenyls)
Thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (furans -2- bases)
Thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -
2- yls) thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -
2- yls) thieno [2,3-d] pyrimidine-4-yl] -2- (2,2,2- trifluoro ethoxies)-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -
2- yls) thieno [2,3-d] pyrimidine-4-yl] -2- (pyridine -2- ylmethoxies)-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -
2- yls) thieno [2,3-d] pyrimidine-4-yl] -2- [(1- methyl isophthalic acid H- pyrazoles -5- bases) methoxyl group]-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -
2- yls) thieno [2,3-d] pyrimidine-4-yl] -2- [(1- ethyl -1H- pyrazoles -5- bases) methoxyl group]-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -
2- yls) thieno [2,3-d] pyrimidine-4-yl] -2- [(2- ethyoxyls pyrimidine-4-yl) methoxyl group]-D-phenylalanine
- 2- [(1- butyl -1H- pyrazoles -5- bases) methoxyl group]-N- [5- { 3- chloro -2- methyl -4- [2- (4- methyl piperazines
Piperazine -1- bases) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -
2- yls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2,2,2- trifluoro ethoxies) pyrimidine-4-yl] methoxyl group }-D- phenylpropyl alcohols
Propylhomoserin
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -
2- yls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1-
Base) thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine
- 2- [(1- tert-butyl -1H- pyrazoles -5- bases) methoxyl group]-N- [5- { 3- chloro -2- methyl -4- [2- (4- methyl
Piperazine -1- bases) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1-
Base) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxy ethyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1-
Base) thieno [2,3-d] pyrimidine-4-yl] -2- { [1- (2,2,2- trifluoroethyls) -1H- pyrazoles -5- bases] methoxyl group }-D- phenylpropyl alcohols
Propylhomoserin
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1-
Base) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (morpholine -4- bases) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1-
Base) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2,2,2- trifluoro ethoxies) pyrimidine-4-yl] methoxyl group }-D- phenylpropyl alcohol ammonia
Acid
- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1-
Base) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
- N- [5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (propyl- 1- alkynes -1- bases) thiophenes
Fen simultaneously [2,3-d] pyrimidine-4-yl] -2- { [1- (2,2,2- trifluoroethyls) -1H- pyrazoles -5- bases] methoxyl group }-D-phenylalanine
- N- [5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (propyl- 1- alkynes -1- bases) thiophenes
Fen simultaneously [2,3-d] pyrimidine-4-yl] -2- { [2- (morpholine -4- bases) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
- N- [5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (propyl- 1- alkynes -1- bases) thiophenes
Fen simultaneously [2,3-d] pyrimidine-4-yl] -2- { [2- (2,2,2- trifluoro ethoxies) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
- N- [5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (propyl- 1- alkynes -1- bases) thiophenes
Fen simultaneously [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
- N- [5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (4- fluorophenyls) thienos
[2,3-d] pyrimidine-4-yl] -2- ({ 2- [2- (2- methoxy ethoxies) phenyl] pyrimidine-4-yl } methoxyl group)-D-phenylalanine
-N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorine
Phenyl) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
Ethyl ester
-N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl-s
1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D- benzene
Alanine ethyl ester
-N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (propyl- 1- alkynes -
1- yls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
Ethyl ester
- N- [5- { 3,5- dichloro- -2,6- dimethyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4-
Fluorophenyl) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D- phenylpropyl alcohol ammonia
Acid
The invention further relates to the preparation method of formula (I) compound, the method is characterized in that using formula (II-a) compound
As raw material：
Wherein Z represents bromine or iodine, and A such as formulas (I) are defined, wherein 1 is connected with chlorine atom, 2 are connected with Z group,
So that formula (II-a) compound is coupled with formula (III) compound：
Wherein R6、R12, E and n such as formulas (I) defined, Alk represents straight or branched (C1-C6) alkyl, obtain formula (IV) and change
Compound：
Wherein R6、R12, A, E and n such as formula (I) defined, Z and Alk as defined hereinabove,
So that formula (IV) compound is further coupled with formula (V) compound：
Wherein R1、R2、R5, X and Y such as formulas (I) defined, RB1And RB2Represent hydrogen atom, straight or branched (C1-C6) alkyl,
Or RB1And RB2The ring optionally to methylate is formed together with carrying their oxygen, obtains formula (VI) compound：
Wherein R1、R2、R5、R6、R12, X, Y, A, E and n such as formula (I) defined, Alk as defined hereinabove,
Alk-O-C (O) the -ester functional group of formula (VI) compound is hydrolyzed, obtains carboxylic acid, its can optionally with formula R7’-OH
Alcohol or formula R7'-Cl chlorinated compound reaction, wherein R7' represent straight or branched (C1-C8) alkyl ,-CHRaRbGroup, virtue
Base, heteroaryl, aryl alkyl (C1-C6) group or heteroaryl alkyl (C1-C6) group, RaAnd RbAs formula (I) defines,
Acquisition formula (I) compound, it can be purified according to conventional isolation techniques, if it is desired, be translated into it
With pharmaceutically acceptable acid or the addition salts of alkali, its isomers optionally is separated into according to conventional isolation techniques,
It should be appreciated that during the above method be considered as it is appropriate whenever, intitation reagents or synthesis
Some groups (hydroxyl, amino ...) of intermediate can be protected, then deprotection and functionalization, according to the requirement of synthesis
It is fixed.
In another embodiment of the present invention, formula (I) compound can use alternative to obtain, this method
It is characterised by using formula (II-b) compound as raw material：
Wherein A such as formulas (I) are defined, wherein 1 is connected with chlorine atom, 2 are connected with iodine atom,
So that formula (II-b) compound is coupled with formula (V) compound：
Wherein R1、R2、R5, X and Y such as formulas (I) defined, RB1And RB2Represent hydrogen atom, straight or branched (C1-C6) alkyl,
Or RB1And RB2The ring to methylate as follows is formed together with carrying their oxygen,
Acquisition formula (VII) compound：
Wherein R1、R2、R5, A, X and Y such as formula (I) defined,
So that formula (VII) compound is further coupled with formula (III) compound：
Wherein R6、R12, E and n such as formulas (I) defined, Alk represents straight or branched (C1-C6) alkyl, obtain formula (VI) and change
Compound：
Wherein R1、R2、R5、R6、R12, X, Y, A, E and n such as formula (I) defined, Alk as defined hereinabove,
Alk-O-C (O) the -ester functional group of formula (VI) compound is hydrolyzed, obtains carboxylic acid, its can optionally with formula R7’-OH
Alcohol or formula R7'-Cl chlorinated compound reaction, wherein R7' represent straight or branched (C1-C8) alkyl ,-CHRaRbGroup, virtue
Base, heteroaryl, aryl alkyl (C1-C6) group or heteroaryl alkyl (C1-C6) group, RaAnd RbAs formula (I) defines,
Acquisition formula (I) compound, it can be purified according to conventional isolation techniques, if it is desired, be translated into it
With pharmaceutically acceptable acid or the addition salts of alkali, its isomers optionally is separated into according to conventional isolation techniques,
It should be appreciated that during the above method be considered as it is appropriate whenever, intitation reagents or synthesis
Some groups (hydroxyl, amino ...) of intermediate can be protected, then deprotection and functionalization, according to the requirement of synthesis
It is fixed.
Formula (II-a), (II-b), (III), (V) compound, R7'-OH and R7'-Cl can both be obtained from business, or also may be used
Obtained with being reacted by those skilled in the art using the conventional chemical described in document.
The pharmaceutical research of the compounds of this invention shows that they have and promotees apoptosis characteristic.Apoptosis is reactivated in cancer cell
The ability of process has great therapeutic potential in cancer and immune and autoimmune disease treatment.
More particularly, the compounds of this invention can be used for the cancer for treating chemotherapy-or radiotherapy-resistance.
In the treatment of cancer of imagination, it can be mentioned that but be not added with any restriction be treatment carcinoma of urinary bladder, the cancer of the brain, breast cancer and
Uterine cancer, chronic lymphoid leukemia, colon cancer, the cancer of the esophagus and liver cancer, Iymphoblastic leukemia, acute myeloid leukaemia,
Lymthoma, melanoma, malignant hematologic disease, myeloma, oophoroma, non-small cell lung cancer, prostate cancer, cancer of pancreas and cellule lung
Cancer.
The invention further relates to the medicine comprising at least one formula (I) compound Yu one or more pharmaceutically acceptable excipient
Use composition.
In the Pharmaceutical composition of the present invention, those can be with it is especially mentioned that suitable for oral, parenteral, intranasal, warp
Skin or transdermal, rectum, the Pharmaceutical composition through tongue, eye or respiratory tract administration, especially tablet or dragee, sublingual tablets,
Sachet, pack (paquets), capsule, lozenge (glossettes), lozenge, suppository, cream, ointment, skin gel
Agent and drinkable or injectable ampoule.
Dosage is according to the sex of patient, age and body weight, method of administration, the property for treating indication or any related controls
Treat and change, its scope is every 24 hours 0.01mg to 1g in single or divided doses.
Moreover, it relates to formula (I) compound and the combination selected from following cancer therapy drug：Genotoxic drugs
(genotoxic agent), mitotic poison, antimetabolite, proteasome inhibitor, kinase inhibitor and antibody, are also related to
And comprising the type combination Pharmaceutical composition and they produce for treating cancer medicine in purposes.
Advantageously, the present invention relates to the combination of formula (I) compound and EGFR inhibitor, further relate to combine comprising the type
Pharmaceutical composition.
In another preferred embodiment, the present invention relates to formula (I) compound and the group of mTOR/PI3K inhibitor
Close, further relate to include the Pharmaceutical composition of the type combination.
In a preferred embodiment, the present invention relates to the combination of formula (I) compound and mek inhibitor, further relate to
Include the Pharmaceutical composition of the type combination.
It is preferred that the present invention relates to the combination of formula (I) compound and HER2 inhibitor, the medicine combined comprising the type is further related to
Use composition.
It is advantageous that the present invention relates to the combination of formula (I) compound and RAF inhibitor, further relate to combine comprising the type
Pharmaceutical composition.
In another embodiment, the present invention relates to the combination of formula (I) compound and EGFR/HER2 inhibitor, also relate to
And include the Pharmaceutical composition of the type combination.
In a preferred embodiment, the present invention relates to the combination of formula (I) compound and taxane, further relate to include
The Pharmaceutical composition of the type combination.
In another embodiment, the present invention relates to formula (I) compound and proteasome inhibitor, immunomodulator or
The combination of alkylating agent, further relate to include the Pharmaceutical composition of the type combination.
The combination of formula (I) compound and cancer therapy drug can be administered either simultaneously or sequentially.The preferred oral route of method of administration, phase
The Pharmaceutical composition answered can allow instantaneous relase or the sustained release of active component.In addition, the compound of combination can also be with
The form administration of two kinds of independent Pharmaceutical compositions, every kind of Pharmaceutical composition contain a kind of active component, or with wherein active
The form administration for the single Pharmaceutical composition that composition mixes.
The compounds of this invention can also together with radiotherapy treatment of cancer with combinations.
Finally, the compounds of this invention may be coupled in monoclonal antibody or its fragment, or may be coupled to and Dan Ke
Grand antibody is related or incoherent scaffolding protein on.
Antibody fragment is appreciated that the piece of Fv, scFv, Fab, F (ab') 2, F (ab'), scFv-Fc types or double antibody
Section, it generally has the antibody identical binding specificity to be originated from them.According to the present invention it is possible to pass through such as stomach cardia
The digestion of the enzyme such as enzyme or papain and/or the present invention is obtained since antibody by the method for electronation cracked disulfide bond
Antibody fragment.On the other hand, the antibody fragment that the present invention is included can be by heredity well-known to those skilled in the art
Recombinant technique obtains, or carries out peptide symthesis acquisition for example, by automatic peptide synthesizer, the automatic peptide synthesizer for example by
Applied Biosystems etc. are provided.
Can or incoherent scaffolding protein related to monoclonal antibody be understood to refer to containing or not comprising immune
Immunoglobulin fold and the protein for producing the binding ability similar to monoclonal antibody.Skilled person will know how selection
Protein scaffolds.More specifically, it is known that such support of selection should have following multiple features (Skerra A.,
J.Mol.Recogn.2000,13,167-187)：The good preservation of germline, the sane framework with known three-dimensional molecular structure
(for example, crystallography or NMR), small size, it is not present or only has low translation and modify, be readily produced, express and purify.It is such
Albumen support can be but not limited to be selected from following structure：Fibronectin and preferable tenth fibronectin type III domain
(FNfn10), lipocalin protein, anticalin (Skerra A., J.Biotechnol.2001,74 (4):257-75), source
From the domain B of staphylococcal protein A protein Z derivative, thioredoxin A or any albumen with repetitive structure domain
Matter, such as " ankyrin repeat (ankyrin repeat) " (Kohl, PNAS 2003,100 (4), 1700-1705), " Qiu
Yu repetitive sequences " (armadillo repeat), " leucine enrichment repetitive sequence " or " quadruple tripeptides repetitive sequence ".Can be with
It is mentioned that and is derived from toxin (such as scorpion, insect, plant or mollusk toxin) or Neuronal Nitric Oxide Synthase (PIN)
Protein inhibitor scaffold de rivative.
Following preparation method and embodiment illustrates the present invention, but it is not limited in any way.
Universal method
All reagents obtained from commercial source can be that can be used without further purification.Anhydrous solvent can be obtained from business
Source need not simultaneously be further dried i.e. usable.
Flash chromatography be equipped with pre-filled silicagel column (RfGold High Performance)
Carried out on ISCO CombiFlash Rf 200i.
Thin-layer chromatography is carried out using the 5 × 10cm plates for scribbling Merck Type 60F254 silica gel.
Microwave heating uses Anton Parr MonoWave or CEMEquipment is carried out.
Preparative HPLC purifying is carried out on Armen Spot liquid chromatographic systems, is used10μM
C18,250mM × 50mM i.d. posts, flow velocity are 118mL min-1, UV diode matrix detection (210-400nm), except non-specifically
Illustrate, using 25mM NH4HCO3The aqueous solution and MeCN are as eluent.
Analytic type LC-MS：The compounds of this invention is being equipped with the quadrupole LC/MS of Agilent 6140 with cation or negative ion electrospray
Carried out on the Agilent HP1200 of spraying ionization mode operation by High Performance Liquid Chromatography/Mass Spectrometry (HPLC-MS) qualitative.Molecule
It is 100 to 1350 to measure scope.Parallel UV Detection wavelengths are 210nm and 254nm.Sample is with 1mM ACN solution or THF/H2O(1:
1) solution provides, 5 μ L circulation injections (loop injection).Lcms analysis is carried out on two instruments, one of them use
Alkaline eluant is carried out, and another uses acidic effluent liquid.
Alkaline LCMS：Gemini-NX, 3 μm, C18,50mM × 3.00mM i.d. posts, 23 DEG C, flow velocity 1mL min-1, use
5mM ammonium hydrogen carbonate (solvent orange 2 A) and acetonitrile (solvent B), gradient since 100% solvent orange 2 A, time by difference/determination with
100% solvent B terminates.
Acid LCMS：ZORBAX Eclipse XDB-C18,1.8 μm, 50mM × 4.6mM i.d. posts, 40 DEG C, flow velocity 1mL
min-1, using 0.02%v/v aqueous formic acids (solvent orange 2 A) and 0.02%v/v formic acid acetonitrile solutions (solvent B), gradient is from 100%
Solvent orange 2 A start, the time by difference/determination is terminated with 100% solvent B.
1H-NMR is determined in Bruker Avance III 500MHz spectrometers and Bruker AvanceIII 400MHz light
Carried out on spectrometer, using DMSO-d6Or CDCl3As solvent.1H NMR datas are the form of δ values, with a few millionths (ppm)
Provide, using dissolvent residual peak (DMSO-d6For 2.50ppm, CDCl3For 7.26ppm) it is used as internal standard.Schizotype is specified as follows：
S (unimodal), d (bimodal), t (triplet), q (quartet), quint (quintet), m (multiplet), br s (width unimodal), dd
(double doublets), td (three doublets), dt (double triplets), ddd (doublet in pairs).
The combination of gas-chromatography and Low Resolution Mass Spectra can be in the gas-chromatographies of Agilent 6850 and Agilent5975C matter
Carried out in spectrum, using the 15m × 0.25mm posts and helium of 0.25 μm of HP-5MS coating as carrier gas.Ion gun：EI+, 70eV, 230
DEG C, quadrupole:150 DEG C, interface：300℃.
HRMS is determined using Shimadzu IT-TOF, 200 DEG C of ion source temperature, and ESI+/-, ionization voltage：(+-)
4.5kV.Mass resolution min.10000.
Elementary analysis is carried out on the elemental analysers of Thermo Flash EA 1112.
Abbreviated list
Abbreviation title
2-Me-THF 2- methyl-tetrahydro furans
Ac acetyl group
Ad adamantyls
Aq. water
AtaPhos bis- (di-tert-butyl (4- dimethylaminophenyls) phosphine) palladium chloride (II)
BuPAd2 butyl-two (adamantane -1- bases) phosphine
Cc. it is dense
DAST diethylaminosulfur trifluorides
Dba dibenzalacetones
DCM dichloromethane
DIPA diisopropylamines
DMA dimethyl acetamides
DME 1,2- dimethoxy-ethanes
DMF dimethylformamides
DMSO dimethyl sulfoxide (DMSO)s
Dppf 1,1'- bis- (diphenylphosphino) ferrocene
Eq. equivalent
Et ethyls
HILIC hydrophilic interaction liquid chromatograies
HMDS HMDSs
iPr isopropyls
LDA lithium diisopropylamides
Me methyl
MeCN acetonitriles
MTBE methyl tert-butylethers
MW microwaves
NBS N-bromosuccinimides
nBu n- butyl
NCS N-chlorosuccinimides
Ph phenyl
PtBu3 x HBF4Three tert-butyl tetrafluoro boric acids
PCy3 x HBF4Thricyclohexyl tetrafluoro boric acid
The phenyl -1 ' of Q-Phos 1,2,3,4,5- five-(di-tert-butyl phosphino-) ferrocene
R.t. room temperature
TBAF tetrabutyl ammonium fluorides
tBu tert-butyls
TEA triethylamines
TFA trifluoroacetic acids
THF tetrahydrofurans
TIPSCl triisopropylsilyl chlorine
XantPhos 4,5- bis- (diphenylphosphino) -9,9- dimethyl xanthenes
Universal method Ia：
By 4- chloros appropriate 1eq.-thieno [2,3-d] pyrimidine derivatives, 2eq. appropriate amino acid derivativges and
2eq.K2CO3 tBuOH:Water 4:Mix in 1 (4mL/mmol), in stirred under reflux temperature (or if necessary to be reacted in MW
In 100 DEG C of stirrings in device) until further conversion is not observed.Then mixture is diluted with water, it is molten using 1M HCl
Liquid is acidified (to pH=1, or to pH=6 in the presence of basic amine group), is extracted with EtOAc, or the precipitation formed after acidifying is led to
It is separated by filtration.In the case of abstraction purification, the organic phase salt water washing of merging is dried over magnesium sulfate, filtering, by filtrate
It is concentrated under reduced pressure.Crude material is by preparative Reverse phase chromatography, using 25mMNH4HCO3The aqueous solution and acetonitrile as eluent,
Unless otherwise indicated.
Universal method Ib：
By 4- chloros appropriate 1eq.-thieno [2,3-d] pyrimidine derivatives, 2eq. appropriate amino acid derivativges and
3eq.K2CO3Mixed in DMSO (10mL/mmol), in 50 DEG C of stirrings until further conversion is not observed.Then will be mixed
Compound is diluted with water, and is acidified (to pH=1, or to pH=6 in the presence of basic amine group) using 1M HCl solutions, is extracted with EtOAc
Take, or the precipitation formed after acidifying is isolated by filtration.In the case of abstraction purification, the organic phase of merging is washed with salt
Wash, it is dried over magnesium sulfate, filtering, filtrate decompression is concentrated.Crude material is by preparative Reverse phase chromatography, using 25mM
NH4HCO3The aqueous solution and acetonitrile are as eluent, unless otherwise indicated.
Universal method Ic：
By 4- chloros appropriate 1eq.-thieno [2,3-d] pyrimidine derivatives, 1.5eq. appropriate amino acid derivativges and
1.5eq.Cs2CO3Mixed in DMSO (6mL/mmol), in 70 DEG C of stirrings until further conversion is not observed.Then will
Mixture is diluted with water, and is acidified using 1M HCl solutions (to pH=1, or to pH=6 in the presence of basic amine group), uses EtOAc
The precipitation formed after extraction, or acidifying is isolated by filtration.In the case of abstraction purification, the organic phase of merging is washed with salt
Wash, it is dried over magnesium sulfate, filtering, filtrate decompression is concentrated.Crude material is by preparative Reverse phase chromatography, using 25mM
NH4HCO3The aqueous solution and acetonitrile are as eluent, unless otherwise indicated.
Universal method IIa：
By the appropriate boronic acid derivatives of 5- (or 6) appropriate 1eq.-iodo- thieno [2,3-d] pyrimidine derivatives and 3eq.
DME (15mL/mmol) is dissolved in, then adds 5eq.K2CO3、0.2eq.Pd2dba3、0.4eq.nBuPAd2With water (5mL/mmol),
By mixture in 60 DEG C in MW reactors stirring until further conversion is not observed.Then volatile matter is removed in vacuum,
Residue is by preparative Reverse phase chromatography, using 25mM NH4HCO3The aqueous solution and acetonitrile are as eluent, unless otherwise saying
It is bright.
Universal method IIb：
The appropriate boronic acid derivatives of the iodo- thienos of the appropriate 5- of 1eq. [2,3-d] pyrimidine derivatives and 5eq. are dissolved in 2-
Me-THF (8mL/mmol), then adds 5eq.K2CO3, 0.1eq.Q-Phos and 0.05eq.Pd2dba3, by mixture in 80 DEG C
Stirring is until being not observed further conversion.Mixture is filtered by Celite pad, filtrate decompression is concentrated.Crude product produces
Thing is by purification by flash chromatography, using heptane and EtOAc as eluent, unless otherwise indicated.
Universal method IIc：
The appropriate boric acid of 5- (or 6) appropriate 1eq.-iodo- thieno [2,3-d] pyrimidine derivatives and 1.1eq. is derived
Thing is dissolved in 2-Me-THF (8mL/mmol), then adds 1.1eq.Ag2CO3With 0.1eq.Pd (PPh3)4, by mixture in 100 DEG C
Stirring is until being not observed further conversion.Mixture is filtered by Celite pad, filtrate decompression is concentrated.Crude product produces
Thing is by purification by flash chromatography, using heptane and EtOAc as eluent, unless otherwise indicated.
Universal method IId：
The appropriate boronic acid derivatives of the iodo- thienos of the appropriate 5- of 1eq. [2,3-d] pyrimidine derivatives and 3eq. are dissolved in two
The ring of oxygen six:Water 2:1 mixture (10mL/mmol), then adds 2eq.Cs2CO3, 5mol%Pd (OAc)2And 0.2eq.PtBu3×
HBF4, by mixture in 120 DEG C in MW reactors stirring until further conversion is not observed.By mixture 1M
HC solution neutralizes, and is extracted with DCM.The organic phase of merging is dried over sodium sulfate, filtering, filter vacuum is concentrated.Crude material leads to
Preparative Reverse phase chromatography is crossed, using 0.1%TFA solution and acetonitrile as eluent, unless otherwise indicated.
Universal method IIIa：
The appropriate boronic acid derivatives of the iodo- thienos of the appropriate 6- of 1eq. [2,3-d] pyrimidine derivatives and 4eq. are dissolved in two
The ring of oxygen six:Water 4:In 1 mixture (10mL/mmol), 2.2eq.Cs is then added2CO3With 0.1eq.Pd (dppf) Cl2, will mix
Thing is in 40 DEG C of stirrings until further conversion is not observed.Then mixture is diluted with water, extracted with DCM.Merge
Organic phase is washed with water, dried over magnesium sulfate, filtering, filtrate decompression is concentrated.Crude material is pure using preparative reverse-phase chromatography
Change, using 25mM NH4HCO3The aqueous solution and acetonitrile are as eluent, unless otherwise indicated.
Universal method IIIb：
The appropriate boronic acid derivatives of the iodo- thienos of the appropriate 6- of 1eq. [2,3-d] pyrimidine derivatives and 3eq. are dissolved in
THF:Water 1:In 1 mixture (10mL/mmol), 3eq.Cs is then added2CO3And 0.1eq.AtaPhos, by mixture in 100 DEG C
Stirring is until being not observed further conversion in MW reactors.Volatiles evaporated in vacuo, residue are anti-by preparative
Phase chromatogram purification, using 25mMNH4HCO3The aqueous solution and acetonitrile are as eluent, unless otherwise indicated.
Universal method IVa：
1eq. preparations 4i is dissolved in anhydrous THF (5mL/mmol) and is cooled to -78 DEG C.It is molten that LDA is added dropwise in ar gas environment
Liquid (1.2eq.2M THF, heptane, EtPh solution), is stirred the mixture for 1.5 hours.Then it is appropriate to add 1.2eq. in -78 DEG C
Pure electrophilic reagent or its solution (the anhydrous THF for being dissolved in 3mL/mmol), mixture is warmed to room temperature.Be stirred for until
Further conversion is not observed.Reactant mixture is by being carefully added into cc.NH4Cl solution is quenched.Mixture is used
MTBE is extracted, and organic layer salt water washing is dried over sodium sulfate, filtering, filtrate decompression is concentrated.Crude material passes through quick color
Spectrum purifying, using heptane and EtOAc as eluent, unless otherwise indicated.
Universal method Va：
Acetal appropriate 1eq. is stirred until being not observed into one in 2M HCl solutions (3mL/mmol) in 60 DEG C
The conversion of step.Reactant mixture is cooled to 0 DEG C, then adds 5.7eq.NaOH by several times.Using 10%K2CO3Solution adjusts pH
Then section adds 2eq. sodium borohydrides, keeping temperature is less than 5 DEG C by several times to 8.Mixture is stirred until not having in 0 DEG C after addition
Have and observe further conversion.Mixture is extracted with EtOAc, the organic phase of merging is dried over sodium sulfate, filtering, by filtrate
It is concentrated under reduced pressure.Crude material is by purification by flash chromatography, using heptane and EtOAc as eluent, unless otherwise indicated.
Universal method Vb：
Step A
It is added dropwise in anhydrous THF (1.5mL/mmol) solution of -78 DEG C of N- alkyl pyrazoles appropriate to 1eq.
1.1eq.nBuLi.Stir the mixture for 30 minutes, be then warmed to 0 DEG C, be stirred for 30 minutes, be then cooled to -78 again
℃.1.1eq.DMF is added dropwise, then warms to room temperature reactant mixture, is stirred for overnight.By mixture cc.NH4Cl is molten
Liquid is quenched.Phase is separated, water layer is extracted with EtOAc.The organic layer of merging is dried over sodium sulfate, filtering, filtrate decompression is concentrated.It is residual
Stay thing to be further purified and be used directly for next step.
Step B
1.3eq. hydroborations are added by several times in EtOH (0.5mL/mmol) solution of -15 DEG C of crude aldehydes appropriate to 1eq.
Sodium, reactant mixture is stirred until further conversion is not observed at room temperature.By mixture down on trash ice and stirring
Mix 16 hours.Filtering precipitate, filtrate decompression is concentrated.Oil phase is separated, water layer is extracted with EtOAc.The organic layer of merging is through sulphur
Sour sodium is dried, and filtering, filtrate decompression is concentrated.If desired, product is further purified through flash chromatography.
Universal method Vc：
Prepared to appropriate 1.2eq. amidine salt and 1eq. in mixtures of the 8a in absolute methanol (0.5mL/mmol) by several times
1.2eq. sodium methoxides are added, by mixture in 75 DEG C of stirrings until further conversion is not observed.Cool down reactant mixture
And it is concentrated under reduced pressure.Water is added into residue, it is extracted with DCM.The organic layer of merging is dried over magnesium sulfate, filtering, will filter
Liquid is concentrated under reduced pressure.Crude material is by purification by flash chromatography, using heptane and EtOAc as eluent, unless otherwise indicated.
Universal method Vd：
Mixing of the 8a in absolute methanol (0.5mL/mmol) is prepared to appropriate 1.2eq. hydrazine or hydrazine hydrochloride and 1eq.
1.2eq. sodium methoxides are added in thing by several times, by mixture in 75 DEG C of stirrings until further conversion is not observed.Will reaction
Mixture is cooled down and is concentrated under reduced pressure.Water is added into residue, it is extracted with DCM.The organic phase of merging is dried over magnesium sulfate,
Filtering, filtrate decompression is concentrated.Crude material is by purification by flash chromatography, using heptane and EtOAc as eluent, unless separately
It is described.
Universal method Ve：
Acetal appropriate 1eq. is stirred until being not observed into one in 1M HCl solutions (3mL/mmol) in 50 DEG C
The conversion of step.Reactant mixture is cooled to 0 DEG C, then adds 2.85eq. solids NaOH by several times.Using 10%K2CO3Solution will
PH is adjusted to 8, then adds 2eq. sodium borohydrides by several times, and keeping temperature is less than 5 DEG C, in 0 DEG C of stirring until be not observed into
The conversion of one step.Mixture is extracted with EtOAc, the organic phase of merging is dried over sodium sulfate, filtering, filtrate decompression is concentrated.
Crude material is by purification by flash chromatography, using heptane and EtOAc as eluent, unless otherwise indicated.
Universal method VI：
In nitrogen environment, by amphyl appropriate 1eq., 2eq. appropriate 01 derivatives and 3eq.PPh3It is dissolved in nothing
Water-toluene (7mL/mmol), 3eq. azoformic acid di-tert-butyl esters are added at room temperature.Then mixture is stirred in 50 DEG C
Mix until further conversion is not observed.Be removed in vacuum volatile matter, residue by purification by flash chromatography, using heptane and
EtOAc is used as eluent (if necessary to add MeOH).If desired, product is further purified by preparative reverse-phase chromatography,
Using 25mMNH4HCO3The aqueous solution and acetonitrile are as eluent, unless otherwise indicated.
Universal method VII：
The appropriate ester derivants of 1eq. are dissolved in THF (15mL/mmol), then add 10eq.LiOH × H2O and water
(15mL/mmol).It is further until being not observed that mixture is stirred to (or if necessary in 60 DEG C of stirrings) at room temperature
Conversion.It will be adjusted using 1M HCl solutions pH to 6, then by mixture salt water washing, be extracted with DCM or EtOAc.Organic layer
It is dried over sodium sulfate, filtering, filtrate decompression is concentrated.Crude material is used by preparative Reverse phase chromatography
25mMNH4HCO3The aqueous solution and acetonitrile are as eluent, unless otherwise indicated.
Universal method VIII：
In nitrogen environment, the appropriate 01 derivatives of appropriate 1eq. indole derivatives and 2eq. are dissolved in dry toluene
(8mL/mmol), mixture is cooled to 0 DEG C, then adds 2eq.2- (tributyl-sub- phosphono) acetonitrile.Then by mixture
It is heated to 100 DEG C and stirs until further conversion is not observed.Volatile matter is removed in vacuum, then adds water (4mL/
Mmol) and 2M NaOH solutions (1mL/mmol), stir the mixture for until further conversion is not observed.Then will be mixed
Compound is acidified to pH=6 using 1M HCl solutions, is extracted with DCM.The organic phase of merging is dried over sodium sulfate, filtering, by filtrate
It is concentrated under reduced pressure.Crude material is by preparative Reverse phase chromatography, using 40mM NH4The OAc aqueous solution (pH=4, using AcOH
Regulation) and acetonitrile as eluent, unless otherwise indicated.
Universal method IXa：
Step A
1eq. preparations 9b is dissolved in dry toluene (8mL/mmol), then adds 1.18eq.PPh at room temperature3、1.1eq.
Appropriate 01 derivatives and 1.18eq. diethyl azodiformates (40% toluene solution).Mixture is stirred at room temperature
Until further conversion is not observed.The sediment obtained is filtered, filtrate uses 10%KHSO4Solution, water, sat.NaHCO3
Solution and water sequential purge.Organic phase is dried over sodium sulfate, filtering, filtrate decompression is concentrated.By residue and ether (5mL/
Mmol) stir together, filter insoluble matter, filtrate decompression is concentrated, obtain crude material.
Step B
Step A product is handled using 10eq.HCl solution (4.9M MeOH solution), it stirred at room temperature straight
To further conversion is not observed.Then mixture is concentrated under reduced pressure.By residue between cold EtOAc and icy water
Distribution, separate phase, the ice-cold 5%KHSO of organic phase4Solution extracts.The aqueous phase of merging uses solid Na2CO3Alkalization, product are used
EtOAc is extracted.Organic phase is dried over sodium sulfate, filtering, filtrate decompression is concentrated, obtains the methyl esters of target product.
Step C
1eq. is dissolved in MeOH (9mL/mmol) obtained from step B methyl esters, then adds 1.05eq.NaOH and water (1mL/
Mmol), mixture is stirred until further conversion is not observed at room temperature.Methanol is removed under reduced pressure, mixture uses
1M HCl solutions neutralize, and then extract it with DCM.Organic phase is dried over sodium sulfate, filtering, filtrate decompression is concentrated, and obtains
The amino acid derivativges of O- alkylations, it, which need not be further purified, directly to use.
Universal method IXb：
Step A
1eq. preparations 9b is dissolved in dry DMF (10mL/mmol), adds 4eq.K at room temperature2CO3It is appropriate with 2eq.
Alkylating reagent.By mixture in 50 DEG C of stirrings until further conversion is not observed.Mixture is diluted with water, then
Extracted with DCM.Organic phase is dried over sodium sulfate, filtering, filtrate decompression is concentrated.Crude material is adopted by purification by flash chromatography
By the use of DCM and methanol as eluent, unless otherwise indicated.
Step B and step C is identical with universal method IXa methods describeds.
Prepare 1a：The bromo- iodo- thienos of 4- chloros -6- [2,3-d] pyrimidines of 5-
Step A：Iodo- 3H- thienos [2,3-d] pyrimidin-4-ones of 6-
433mL acetic acid, 13mL sulphur are added to being equipped with the 2L round-bottomed flasks of mechanical agitator, thermometer and reflux condenser
The solution of acid and 87mL water.Into the solution of the stirring add 69.3g3H- thienos [2,3-d] pyrimidin-4-one (0.46mol),
51.9g periodic acid (0.23mol) and 104g iodine (0.41mol), are heated to 60 DEG C 1 hour.The suspension of acquisition is cooled down
To room temperature, filtering, with acetic acid and water (5:1) mixture washing, is then washed with ether.By the ecru crystalline solid of acquisition
It is air-dried.1H NMR(500MHz,DMSO-d6)δ:12.57(br s,1H),8.09(s,1H),7.65(s,1H)
Step B：The iodo- thienos of 4- chloros -6- [2,3-d] pyrimidine
To outfit mechanical agitator, thermometer and reflux condenser and CaCl2113mL is added in the 1L round-bottomed flasks of-pipe
Phosphoryl chloride phosphorus oxychloride and 35mL N, accelerine (0.29mol).The 6- for adding 75.54g in 5 minutes by several times into mixture is iodo-
3H- thienos [2,3-d] pyrimidin-4-one (0.27mol).Reactant mixture is stirred 1 hour in 105 DEG C.By the suspension of acquisition
Liquid is cooled to 10 DEG C, filtering, is washed with hexane.Crude material is added in frozen water and stirred 10 minutes, filtering, with cold water, second
Ether washs, and is air-dried.Obtain ecru crystalline solid.1H NMR(400MHz,DMSO-d6)δ：8.89(s,1H),7.98(s,
1H)
Step C：Prepare 1a
600mL acetonitriles are added to being equipped with the 2L round-bottomed flasks of mechanical agitator, thermometer and bubbler.Add 84.9g
The iodo- thienos of 4- chloros -6- [2,3-d] pyrimidine (0.29mol), 50.9g NBS (0.29mol) and 8.5mL tetrafluoro boric acid ether
Compound.Reactant mixture is stirred at room temperature 16 hours.Add 22.9g (0.12mol) NBS in three times into mixture.
Suspension is cooled to 0 DEG C and is stirred for 1 hour, filtering precipitate, is washed, is air-dried with acetonitrile.Obtain as ecru knot
The product of brilliant solid.1H NMR(500MHz,DMSO-d6)δ：8.88(s,1H)
Prepare 1b：Iodo- thieno [2,3-d] pyrimidines of 4- chloros -5,6- two
Step A：Iodo- 3H- thienos [2,3-d] pyrimidin-4-ones of 5,6- bis-
Added into the slurries of 3H- thienos [2,3-d] pyrimidin-4-one (396mMol) for the 61.3g being sufficiently stirred
92.4g periodic acid (405mMol), 1L acetic acid, 200mL water, the 6mL concentrated sulfuric acid and 203g iodine (799mMol).By reactant mixture
It is heated to 110 DEG C and stirs 3 hours.Suspension is cooled to room temperature, then add 940mL ether, by mixture in 10 DEG C again
Stirring 30 minutes.Filtering precipitation, with the 2 of ether and ethanol:1 mixture (100mL) washs, finally washed with ether (3 ×
250mL), then it is air-dried, obtains the product for brown powder.1H NMR(500MHz,DMSO-d6)δ:12.60(br
s,1H),8.13(s,1H)
Step B：Prepare 1b
To the 180g being sufficiently stirred iodo- 3H- thienos [2,3-d] pyrimidin-4-ones (445mMol) of 5,6- bis- in 2.5L phosphorus
64mL N, accelerine are added in slurries in acyl chlorides.Reactant mixture is heated to 105 DEG C and stirred 1.5 hours.
The suspension of acquisition is cooled to room temperature, 1.5L hexanes is added, is stirred for 20 minutes.Filtering precipitation, (3 are washed with hexane
× 500mL) and water (3 × 100mL) washing, then it is air-dried, obtains the product for grey crystalline solid.1H NMR
(400MHz,DMSO-d6)δ：8.88(s,1H)
Prepare 1c：The iodo- thienos of 4- chloros -5- [2,3-d] pyrimidine
52.8g is prepared into 1b (125mMol) and is dissolved in the anhydrous THF of 400mL, is cooled in 0 DEG C of .15 minute and adds 100mL'stBuMgCl (200mMol, 2M diethyl ether solution).Then 50mL water is added, solution is removed and is concentrated under reduced pressure.Crude material is existed
Acetonitrile and water (3:1) it is ultrasonic in mixture, then it is collected by filtration.1H NMR(400MHz,DMSO-d6)δ：8.95(s,
1H),8.45(s,1H)
Prepare 2a：4- chloros -6- ethyls -5- iodo- thieno [2,3-d] pyrimidine
Step A：6- ethyl -3H- thienos [2,3-d] pyrimidin-4-one
By 701g 2- amino -5- ethyl-thiophen -3- carboxylic acid, ethyl esters (3.52mol) and the mixture of 2200mL formamides
200 DEG C are heated to, low boiling point solvent is distilled off.After 2 hours, another 250mL formamide is added, by mixture in phase equality of temperature
It is stirred under degree 1 hour, then stirs 16 hours at room temperature.The mixture of acquisition is poured into 7.5L water, filtering precipitation, used
1.5L toluene and 3L water washings, then it is air-dried the product obtained as brown crystalline solid.1H NMR(500MHz,DMSO-d6)
δ:12.40(br s,1H),8.05(s,1H),7.11(t,1H),2.85(qd,2H),1.27(t,3H)
Step B：Iodo- 3H- thienos [2,3-d] pyrimidin-4-ones of 6- ethyls -5-
By 301g 6- ethyl -3H- thienos [2,3-d] pyrimidin-4-one (1.67mol), 847g iodine (3.34mol),
The mixture of 1040g silver sulfates (3.34mol) and 1.7L ethanol stirs 3 days at room temperature.The sediment obtained is filtered, uses ethanol
(3 × 400mL) is washed.Using following method from filter cake eluted product：Filter cake and 800mL DMF mono- are arised from into 50 DEG C of stirrings 1
Hour, then filter suspension.This is sequentially repeated 6 times.The organic layer of merging is evaporated to dryness, obtained as tan crystalline solid
Product.
Step C：Prepare 2a
The mixture of the 880mL phosphoryl chloride phosphorus oxychlorides of stirring and 102mL DMA is heated to 95 DEG C, in this temperature
Under rapidly join 220g iodo- 3H- thienos [2,3-d] pyrimidin-4-ones (0.719mol) of 6- ethyls -5-, then stir 15 points
Clock.Reactant mixture is cooled to 80 DEG C, poured into the water (1L) of stirring, trash ice (2kg) and DCM (700mL) mixture.Will
The mixture of acquisition is stirred for 30 minutes, while keeping temperature is less than 20 DEG C.Phase is separated, inorganic layer extracts (100mL) with DCM,
Organic layer is washed with water (100mL).The organic layer of merging is dried over magnesium sulfate, filtering, filtrate decompression is concentrated, obtained as brown
The product of crystalline solid.1H NMR(400MHz,DMSO-d6)δ：8.79(s,1H),3.02(q,2H),1.39(t,3H)
Prepare 2b：5- bromo- 4- chloros -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine
75.08g is prepared to 1a (200mMol), 53.63g 2- (4- fluorophenyls) -4,4,5,5- tetramethyls -1,3,2- two
Oxa- ring pentaborane (240mMol), 130g cesium carbonates (400mMol), 2.245g Pd (OAc)2(10mMol) and 8.50g'stBuX-Phos (20mMol) is placed in 2L flasks.600mL THF and 200mL water is added, then in 70 DEG C in ar gas environment
It is stirred overnight.THF is evaporated, product is then collected by filtration.By crude material in 250mL acetonitriles it is ultrasonic, filter again.So
After prepare 2b in EtOH/THF (2:1) crystallized in.1H NMR(400MHz,DMSO-d6)δ：9.02(s,1H),7.80-7.77(m,
2H),7.47-7.43(m,2H)
Prepare 2c：The iodo- 6- of 4- chloros -5- (propyl- 1- alkynyls)-thieno [2,3-d] pyrimidine
42.24g is prepared to 1b (100mMol), 3.509g Pd (PPh3)2Cl (5mMol) and 1.904g CuI
(10mMol) is dissolved in 400mL DIPA, and propine is then passed through into reactant mixture, and it is stirred until not having at room temperature
It was observed that further conversion.Volatiles evaporated in vacuo, crude material is by purification by flash chromatography, using heptane/EtOAc conducts
Eluent.1H NMR(400MHz,DMSO-d6)δ：8.92(s,1H),2.25(s,3H)
Prepare 2d：The iodo- 6- isopropyls of 4- chloros -5--thieno [2,3-d] pyrimidine
Step A：Iodo- 3H- thienos [2,3-d] pyrimidin-4-ones of 6- isopropyls -5-
By 2.858g (14.7mMol) 6- isopropyl -3H- thienos [2,3-d] pyrimidin-4-one, 7.468g (29.4mMol)
The mixture of iodine, 9.175g (29.4mMol) silver sulfates and 55mL ethanol stirs 3 days at room temperature.By mixture Et2O is dilute
Release, filter the sediment of acquisition, it, which need not be further purified, directly to use.
1H NMR(400MHz,DMSO-d6)δ:12.49 (br s, 1H), 8.11 (s, 1H), 3.35 (m, 1H, by H2O signals
Cover), 1.28 (d, 6H)
MS(M-H)：319.0
Step B：Prepare 2d
By 15mL (161mMol) phosphoryl chloride phosphorus oxychlorides and 1.9mL (14.7mMol) N, the mixture of accelerine is heated to 95
DEG C, iodo- 3H- thienos [2, the 3-d] pyrimidin-4-ones (0.719mol) of 25.9g (14.7mMol) 6- isopropyls -5- are rapidly joined,
Then it is stirred at a temperature of this 15 minutes.Reactant mixture is cooled to 80 DEG C, pours into the frozen water (300g) and EtOAc of stirring
In the mixture of (200mL).The mixture of acquisition is stirred for 30 minutes, while keeping temperature is less than 20 DEG C.Phase is separated, it is inorganic
Layer is extracted (100mL) with EtOAc, organic layer water and NaHCO3Solution washs.The organic layer of merging is dried over magnesium sulfate, mistake
Filter, filtrate decompression is concentrated, and by purification by flash chromatography, using heptane and EtOAC as eluent, obtains target product.
1H NMR(400MHz,CDCl3)δ：8.78 (s, 1H), 3.63 (heptet, 1H), 1.41 (d, 6H)
MS(M+H)：339.0
Prepare 3a：(2R) -2- [(the iodo- thienos of 6- ethyls -5- [2,3-d] pyrimidine-4-yl) amino] -3- phenyl-propionics
Using universal method Ia, 2a is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains as appropriate amino acid derivativges and prepares 3a.
1H NMR(500MHz,DMSO-d6)δ：8.44(s,1H),7.45(d,1H),7.30-7.20(m,5H),5.07(m,
1H),3.35(dd,1H),3.16(dd,1H),2.82(q,2H),1.22(t,3H)
HRMS C17H16IN3O2S calculated value：453.0008；Measured value：454.0064(M+H)
Prepare 4a：4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6-
Iodo- thieno [2,3-d] pyrimidine
Step A：4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] thiophene
And [2,3-d] pyrimidine
Using universal method IIa, 1c is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, B4 is prepared and makees
For appropriate boronic acid derivatives, by purification by flash chromatography product, using DCM and MeOH as eluent, 4- chloros -5- is obtained
[3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] thieno [2,3-d] pyrimidine.1H NMR
(400MHz,DMSO-d6)δ：8.98(s,1H),7.97(s,1H),7.22(d,1H),7.09(s,1H),4.25-4.16(m,
2H),2.76(t,2H),2.54(br s,4H),2.32(br s,4H),2.14(s,3H),2.06(s,3H)
Step B：Prepare 4a
By 10.935g 4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl]
Thieno [2,3-d] pyrimidine (25mMol) is dissolved in the anhydrous THF of 250mL, is cooled to -78 DEG C.In ar gas environment, it is added dropwise 25mL's
LDA solution (50mMol, 2M THF, heptane, ethyl benzole soln), is stirred the mixture for 15 minutes.Then in -78 DEG C of additions
12.69g (50mMol) iodine, mixture is warmed to room temperature.Then mixture is diluted with EtOAc, uses NH4Cl solution washs,
Then Na is used2S2O3Solution washs, dried over sodium sulfate, filtering, is concentrated under reduced pressure.Crude material is used by purification by flash chromatography
DCM and MeOH is obtained as eluent and is prepared 4a.1H NMR(500MHz,DMSO-d6)δ：8.93(s,1H),7.15(d,1H),
7.13(d,1H),4.22(t,2H),2.77(t,2H),2.56(br s,4H),2.34(br s,4H),2.16(s,3H),2.00
(s,3H)
Prepare 4b：4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6-
(2- furyls) thieno [2,3-d] pyrimidine
Using universal method IIa, 4a is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives, 2- (2- furans
Mutter base) -4,4,5,5- tetramethyls -1,3,2- dioxaborolanes obtain as appropriate boronic acid derivatives and prepare 4b.MS：
(M+H)=503.0
Prepare 4c：4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6-
(the fluoro- 2- furyls of 5-) thieno [2,3-d] pyrimidine
Using universal method IIIa, 4a is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives, 2- (5-
Fluoro- 2- furyls) -4,4,5,5- tetramethyls -1,3,2- dioxaborolanes are prepared as appropriate boronic acid derivatives
4c。
1H NMR(500MHz,DMSO-d6)δ：8.93(s,1H),7.24(d,1H),7.18(d,1H),5.92(dd,1H),
5.68(t,1H),4.23(t,2H),2.79(t,2H),2.58(br s,4H),2.38(br s,4H),2.19(s,3H),2.05
(s,3H)
HRMS C24H23N4O2FSCl2Calculated value：520.0903；Measured value：521.0972(M+H)
Prepare 4d：2- chloros -4- (the iodo- thienos of 4- chloros -6- [2,3-d] pyrimidine -5- bases) -3- methyl-phenols
Step A：[2- chloros -4- (4- chloro thiophenes simultaneously [2,3-d] pyrimidine -5- bases) -3- methyl-phenoxvs]-three isopropyls
Base-silane
Using universal method IIa, 1c is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, B3 is prepared and makees
For appropriate boronic acid derivatives, [2- chloros -4- (4- chloro thiophenes simultaneously [2,3-d] pyrimidine -5- bases) -3- methyl-benzene oxygen is obtained
Base]-triisopropyl-silane.1H NMR(400MHz,DMSO-d6)δ：8.95(s,1H),7.98(s,1H),7.13(d,1H),
6.91(d,1H),2.05(s,3H),1.40-1.29(m,3H),1.10(dd,18H)
Step B：[2- chloros -4- (4- chloro -6- iodothiophens simultaneously [2,3-d] pyrimidine -5- bases) -3- methyl-phenoxvs]-three
Isopropyl-silane
33.7g [2- chloros -4- (4- chloro thiophenes simultaneously [2,3-d] pyrimidine -5- bases) -3- methyl-phenoxvs]-three is different
Propyl group-silane (72mMol) is dissolved in the anhydrous THF of 300mL, is cooled to -78 DEG C.43.2mL LDA solution is added dropwise in ar gas environment
(86.4mMol, 2M THF, heptane, ethyl benzole soln), is stirred the mixture for 15 minutes.Then 23.8g iodine is added in -78 DEG C
(93.7mMol), mixture is warmed to room temperature.Then mixture is diluted with EtOAc, uses NH4Cl solution washs, Ran Houyong
Na2S2O3Solution washs.Organic layer is dried over sodium sulfate, filtering, is concentrated under reduced pressure.1H NMR(400MHz,DMSO-d6)δ：8.91
(s,1H),7.05(d,1H),6.97(d,1H),1.99(s,3H),1.39-1.30(m,3H),1.10(dd,18H)
Step C：Prepare 4d
By 10.0g [2- chloros -4- (4- chloro -6- iodothiophens simultaneously [2,3-d] pyrimidine -5- bases) -3- methyl-benzene oxygen
Base]-triisopropyl-silane (16.85mMol) is dissolved in the anhydrous THF of 100mL, add 18.5mL TBAF solution (18.5mMol, 1M
THF solution), mixture is stirred at room temperature 10 minutes.Then mixture is diluted with EtOAc, with 1M HCl solutions and
Salt water washing.Organic layer is dried over sodium sulfate, filtering, is concentrated under reduced pressure.Crude material by purification by flash chromatography, using heptane and
EtOAc is obtained as eluent and is prepared 4d.HRMS C13H7Cl2IN2OS calculated values：435.8701, measured value：436.8780(M+
H)
Prepare 4e：2- [2- chloros -4- (the iodo- thienos of 4- chloros -6- [2,3-d] pyrimidine -5- bases) -3- methyl-benzene oxygen
Base]-N, N- dimethyl-ethylamines
Using universal method VI, 4d is prepared as appropriate phenol derivatives, and N, N- dimethylethanolamines are as appropriate
Alcohol, obtain and prepare 4e.S(M+H)：508.0
Prepare 4f：2- chloros -4- [4- chloros -6- (3- thienyls) thieno [2,3-d] pyrimidine -5- bases] -3- methyl-benzene
Phenol
Using universal method IIIa, 4d is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives, thiophene -3-
Pinacol borate obtains as appropriate boronic acid derivatives and prepares 4f.MS(M+H)：393.0
Prepare 4g：4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6-
(3- thienyls) thieno [2,3-d] pyrimidine
Using universal method VI, 4f is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives, 2- (4- methyl
Piperazine -1- bases) ethanol as appropriate alcohol, obtains and prepares 4g.
1H NMR(500MHz,DMSO-d6)δ：8.94(s,1H),7.60(dd,1H),7.56(dd,1H),7.19(d,1H),
7.12(d,1H),6.79(dd,1H),4.21(t,1H),2.77(t,1H),2.56(br,4H),2.33(br,4H),2.15(s,
3H),2.04(s,3H)
HRMS C24H24Cl2N4OS2Calculated value：518.0769；Measured value：519.0852(M+H)
Prepare 4h：4- [2- [2- chloros -4- [4- chloros -6- (3- thienyls) thieno [2,3-d] pyrimidine -5- bases] -3-
Methyl-phenoxv] ethyl] morpholine
Using universal method VI, prepare 4f and obtained as appropriate phenol derivatives, 2- morpholinoes ethanol as appropriate alcohol
4h must be prepared.
Prepare 4i：4- chloros -5- (1- naphthyls) thieno [2,3-d] pyrimidine
Step A：2- amino -4- (1- naphthyls) thiophene -3- Ethyl formates
By 50.00g 1- (1- naphthyls) ethyl ketone (293.8mMol), 43.66g cyan-acetic ester (386.0mMol),
18.84g sulphur (587.5mMol), 8.4mL AcOH and 38.39g morpholines are dissolved in 300mL EtOH, in 60 DEG C of stirrings until not having
It was observed that further conversion.Volatile matter is removed in vacuum, residue is by purification by flash chromatography, using heptane and EtOAc conducts
Eluent, obtain 2- amino -4- (1- naphthyls) thiophene -3- Ethyl formates.HRMS C17H15NO2S calculated values：297.0823；Actual measurement
Value：298.0891(M+H)
Step B：5- (1- naphthyls) -3H- thienos [2,3-d] pyrimidin-4-one
9.40g 2- amino -4- (1- naphthyls) thiophene -3- Ethyl formates (31.6mMol) are dissolved in 45mL formamides, in
200 DEG C of stirrings are until being not observed further conversion.Mixture is cooled to room temperature, is poured into water.Filtering precipitation is consolidated
Body, it is washed with water, then dries, obtains 5- (1- naphthyls) -3H- thienos [2,3-d] pyrimidin-4-one.HRMS C16H10N2OS is counted
Calculation value：278.0514；Measured value：279.0582(M+H)
Step C：Prepare 4i
By 8.50g 5- (1- naphthyls) -3H- thienos [2,3-d] pyrimidin-4-one (30.5mMol), 4.07g N, N- bis-
Methylaniline (33.6mMol) and 22.8mL POCl3s (244mMol) stir 1 hour in 100 DEG C.Mixture is cooled to room
Temperature, pour into the frozen water of stirring.The solid of precipitation is filtered, is recrystallized in acetonitrile, obtains and prepares 4i.HRMS C16H9N2SCl is counted
Calculation value：296.0175；Measured value：297.0255(M+H)
Prepare 4j：4- chloros -5- (3- chloro -2- methylphenyls) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine
Using universal method IIb, 2a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, (3- chloros-
2- methylphenyls) boric acid as appropriate boronic acid derivatives, obtains and prepares 4j.
1H NMR(400MHz,DMSO-d6)δ：8.89(s,1H),7.55(dd,1H),7.33(t,1H),7.23(dd,1H),
2.65(m,2H),2.03(s,3H),1.17(t,3H)
HRMS C15H12Cl2N2S calculated values：322.0098；Measured value：323.0164(M+H)
Prepare 4k：4- chloro -6- ethyls -5- (1- naphthyls) thieno [2,3-d] pyrimidine
Using universal method IIb, 2a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 1- naphthalene boronic acids
DOPCP obtains as appropriate boronic acid derivatives and prepares 4k.
1H NMR(400MHz,DMSO-d6)δ：8.91(s,1H),8.07(dd,1H),8.03(dm,1H),7.63(dd,
1H),7.55(tm,1H),7.51(dd,1H),7.44(tm,1H),7.33(dm,1H),2.61(q,2H),1.13(t,3H)
HRMS C18H13ClN2S calculated values：324.0488；Measured value：325.0562(M+H)
Prepare 4l：4- chloro -6- methyl -5- (1- naphthyls) thieno [2,3-d] pyrimidine
Using universal method IVa, methyl-iodine obtains as appropriate electrophilic reagent and prepares 4l.
1H NMR(400MHz,DMSO-d6)δ：8.90(s,1H),8.04(dd,2H),7.63(dd,1H),7.54(td,
1H),7.49(dd,1H),7.43(td,1H),7.32(d,1H),2.28(s,3H)
MS(M+H)：311.0
Prepare 4m：[4- chloros -5- (1- naphthyls) thieno [2,3-d] pyrimidine -6- bases] methanol
Step A：4- chloros -5- (1- naphthyls) thieno [2,3-d] pyrimidine -6- formaldehyde
Using universal method IVa, DMF obtains 4- chloros -5- (1- naphthyls) thieno as appropriate electrophilic reagent
[2,3-d] pyrimidine -6- formaldehyde.1H NMR(400MHz,CDCl3)δ：9.65(s,1H),9.00(s,1H),8.07(d,1H),7.99
(d,1H),7.68-7.52(m,3H),7.47(t,1H),7.33(d,1H)
Step B：Prepare 4m
4- chloros -5- (1- naphthyls) thieno [2,3-d] pyrimidine -6- formaldehyde is dissolved in THF:MeOH 1:1(4mL/
Mmol), 3eq.NaBH is added in 0 DEG C4.Stir the mixture for 10 minutes, be then quenched with 1M citric acids.By mixture DCM
Extraction, it is dried over sodium sulfate with sodium bicarbonate aqueous solution and salt water washing, filtering, filter vacuum is concentrated.Crude material passes through
Purification by flash chromatography, using heptane and EtOAc as eluent, obtain and prepare 4m.
1H NMR(400MHz,DMSO-d6)δ：8.92(s,1H),8.06(d,1H),8.03(d,1H),7.62(m,1H),
7.58-7.49(m,2H),7.44(m,1H),7.35(d,1H),5.99(t,1H),4.54(dd,1H),4.33(dd,1H)
MS(M+H)：327.0
Prepare 4n1 and prepare 4n2：1- [4- chloros -5- (1- naphthyls) thieno [2,3-d] pyrimidine -6- bases] ethanol
Using universal method IVa, acetaldehyde obtains the crude product as non-enantiomer mixture as appropriate electrophilic reagent
Product, sequentially separated by continuous flash chromatography, eluent is used as using DCM- acetone and heptane-MTBE.Diastereomer pair
Eluting order be identical in two elution systems.Obtain and prepare 4n1, be that the diastereoisomer more early eluted (disappears outside
Revolve body).
1H NMR(400MHz,CDCl3)δ：8.85(s,1H),7.99(d,1H),7.95(d,1H),7.60-7.49(m,
2H),7.46-7.34(m,3H),4.84(m,1H),2.06(d,1H)1.53(d,3H)
MS(M+H)：341.0
Obtain and prepare 4n2, be the diastereoisomer (racemic modification) of later elution.
1H NMR(400MHz,CDCl3)δ：8.85(s,1H),7.99(d,1H),7.94(d,1H),7.60-7.49(m,
2H),7.46(dd,1H)7.43-7.37(m,1H),7.27(overlap,1H),4.98(m,1H),2.14(d,1H)1.35(d,
3H)
MS(M+H)：341.0
Prepare 4o：1- [4- chloros -5- (1- naphthyls) thieno [2,3-d] pyrimidine -6- bases] ethyl ketone
157mg is worn into this Martin's oxidant (0.37mMol) and is dissolved in 2mL DCM, is then added and is prepared 4n1 and prepare 4n2's
Mixture (120mg, 0.35mMol, is dissolved in 10mL DCM), is stirred the mixture for until further conversion is not observed.
Then mixture is diluted with DCM, with NaOH and NaHCO3Solution and salt water washing, dried over sodium sulfate, filtering, decompression are dense
Contracting.Crude material, using heptane and EtOAc as eluent, is obtained by purification by flash chromatography and prepares 4o.
1H NMR(500MHz,DMSO-d6)δ：9.09(s,1H),8.16(dd,1H),8.08(d,1H),7.72-7.65(m,
2H),7.62-7.57(m,1H),7.52-7.43(m,2H),1.71(s,3H)
MS(M+H)：339.0
Prepare 4p：2- [4- chloros -5- (1- naphthyls) thieno [2,3-d] pyrimidine -6- bases] propan-2-ol
Using universal method IVa, acetone obtains as appropriate electrophilic reagent and prepares 4p.
1H NMR(400MHz,CDCl3)δ：8.80(s,1H),7.98(d,1H),7.92(d,1H),7.59-7.46(m,
2H),7.46-7.34(m,2H),7.30(d,1H),2.53(br s,1H),1.54(s,3H),1.21(s,3H)
MS(M+H)：355.0
Prepare 4q：4- chloro -6- isopropyls -5- (1- naphthyls) thieno [2,3-d] pyrimidine
Step A：6- isopropyls -5- (1- naphthyls) -3H- thienos [2,3-d] pyrimidin-4-one
250mg is prepared to 4p (0.705mMol) and 1.75mL Et3SiH (10.9mMol) is placed in flask, using 10mL
TFA in -10 DEG C processing.Then mixture is stirred until further conversion is not observed in 50 DEG C.Then mixture
Diluted with DCM, with solid K2CO3And NaHCO3Solution neutralizes.After separating phase, organic phase salt water washing is dried over sodium sulfate,
Filtering, it is concentrated in vacuo, obtains 6- isopropyls -5- (1- naphthyls) -3H- thienos [2,3-d] pyrimidin-4-one, be crude intermediate.
MS(M+H)：321.0
Step B：Prepare 4q
In ar gas environment, 2mL phosphoryl chloride phosphorus oxychlorides and 0.161mL DMA (1.27mMol) are placed in flask
In, added by several times into mixture in 5 minutes 1.22g 6- isopropyls -5- (1- naphthyls) -3H- thienos [2,3-d] pyrimidine -
4- ketone.By reactant mixture in 100 DEG C of stirrings until further conversion is not observed.Mixture is cooled to room temperature, fallen
In the frozen water for entering stirring.Aqueous medium is obtained by being carefully added into solid NaHCO3Neutralize.After gas overflowing stops, product is used
DCM is extracted three times.The organic layer of merging is dried over sodium sulfate, filtering, is concentrated under reduced pressure.Crude material by purification by flash chromatography,
Using heptane and EtOAc as eluent, obtain and prepare 4q.
1H NMR(500MHz,CDCl3)δ：8.80(s,1H),7.97(d,1H),7.94(d,1H),7.57(dd,1H),
7.54-7.49 (m, 1H), 7.42-7.37 (m, 2H), 7.34 (d, 1H), 3.02 (heptet, 1H), 1.31 (d, 3H), 1.20 (d,
3H)
MS(M+H)：339.0
Prepare 4r：4- chloros -6- (difluoromethyl) -5- (1- naphthyls) thieno [2,3-d] pyrimidine
0.250g 4- chloros -5- (1- naphthyls) thieno [2,3-d] pyrimidine -6- formaldehyde (is prepared into step A in 4m synthesis
Intermediate, 0.77mMol) 7mL DCM are dissolved in, then add 270 μ lDAST (1.16mMol).Mixture is stirred at room temperature
Until further conversion is not observed.Then mixture is diluted with DCM, be washed with water, then use NaHCO3Solution and salt
Water washing.Organic phase is dried over sodium sulfate, filtering, is concentrated under reduced pressure.Crude material by purification by flash chromatography, using heptane and
EtOAc is obtained as eluent and is prepared 4r.
1H NMR(500MHz,CDCl3)δ：8.97(s,1H),8.04(d,1H),7.97(d,1H),7.62-7.54(m,
2H),7.49-7.43(m,2H),7.28(d,1H),6.47(t,1H)
MS(M+H)：347.0
Prepare 4s：The iodo- 5- of 4- chloros -6- (1- naphthyls) thieno [2,3-d] pyrimidine
Using universal method IVa, iodine obtains as appropriate electrophilic reagent and prepares 4s.
1H NMR(400MHz,DMSO-d6)δ：8.94(s,1H),8.10(dm,1H),8.05(dm,1H),7.66(dm,
1H),7.56(tm,1H),7.48(dd,1H),7.44(tm,1H),7.31(dm,1H)
HRMS C16H8N2SC lI calculated values：421.9141；Measured value：422.9211(M+H)
Prepare 4t：4- chloros -5- (3- chloro -2- methylphenyls) the iodo- thienos of -6- [2,3-d] pyrimidine
Step A：4- chloros -5- (3- chloro -2- methylphenyls) thieno [2,3-d] pyrimidine
Using universal method IIb, 1c is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, (3- chloros-
2- methylphenyls) boric acid as appropriate boronic acid derivatives, obtains 4- chloros -5- (3- chloro -2- methylphenyls) thieno
[2,3-d] pyrimidine.1H NMR(400MHz,CDCl3)δ：8.89(s,1H),7.47(dd,1H),7.43(s,1H),7.20(t,
1H),7.14(dd,1H),2.14(s,3H)
Step B：Prepare 4t
Using universal method IVa, 4- chloros -5- (3- chloro -2- methylphenyls) thieno [2,3-d] pyrimidine replaces system
Standby 4i, iodine obtain as appropriate electrophilic reagent and prepare 4t.1H NMR(400MHz,CDCl3)δ：8.82(s,1H),7.52
(dd,1H),7.25(t,1H),7.05(dd,1H),2.09(s,3H)
Prepare 4u：4- chloros -5- (3- chloro -2- methylphenyls) -6- isopropyls-thieno [2,3-d] pyrimidine
Using universal method IIb, 2d is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, (3- chloros-
2- methylphenyls) boric acid as appropriate boronic acid derivatives, obtains and prepares 4u.
1H NMR(400MHz,DMSO-d6)δ：8.90(s,1H),7.56(dd,1H),7.34(t,1H),7.29-7.22(m,
1H), 2.94 (heptet, 1H), 2.04 (s, 3H), 1.26 (d, 3H), 1.22 (d, 3H)
HRMS C16H14N2SCl2Calculated value：336.0255；Measured value：337.0335(M+H)
Prepare 4v：4- chloro -6- ethyls -5- (1H- indoles -4- bases) thieno [2,3-d] pyrimidine
By 0.664g prepare 2a (2.0mMol), 0.400g 1H- indoles -4- ylboronic acids (1.2eq, 2.4mMol),
44.9mg Pd (OAc)2(10mol%, 0.2mMol), 152mg PCy3×HBF4(20mol%, 0.4mMol), 1.96g's
Cs2CO3The mixture of (3.0eq, 6.0mMol) in 7.3mL dimethoxy-ethanes and 7.3mL water is in microwave reactor in 100
DEG C heating until further conversion is not observed.Crude product reactant mixture is filtered by Celite pad, with 2 × 10mL
MTBE and 2 × 10mL water washings.Two layers of filtrate is separated, organic layer salt water washing is then dried over sodium sulfate, filtering, vacuum
Concentration.Residue, using water (containing 0.1%TFA) and acetonitrile as eluent, is made by preparative Reverse phase chromatography
Standby 4v.
1H NMR(400MHz,DMSO-d6)δ:11.22(br s,1H),8.87(s,1H),7.49(dm,1H),7.32(m,
1H),7.19(dd,1H),6.95(dm,1H),5.96(m,1H),2.67(m,2H),1.14(t,3H)
HRMS calculated values C16H12ClN3S：313.0440；Measured value：314.0508(M+H)
Prepare 4w：4- chloros -5- (1- naphthyls) -6- vinyl-thieno [2,3-d] pyrimidine
Using universal method IIc, 4s is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives, vinyl boron
Sour pinacol ester obtains as appropriate boronic acid derivatives and prepares 4w.
1H NMR(500MHz,DMSO-d6)δ：8.95(s,1H),8.09(d,1H),8.05(d,1H),7.65(dd,1H),
7.56(t,1H),7.52(dd,1H),7.45(t,1H),7.35(d,1H),6.34(dd,1H),5.90(d,1H),5.45(d,
1H)
HRMS C18H11ClN2S calculated values：322.0331；Measured value：323.0415(M+H)
Prepare 4x：4- chloros -5- (1- naphthyls) -6- [(E/Z) -propyl- 1- alkenyls] thieno [2,3-d] pyrimidine
Step A：5,5- dimethyl -2- [(Z/E) -propyl- 1- alkenyls] -1,3,2- dioxoborinanes
To 0.172g (Z) -propyl- 1- alkene -1- ylboronic acids (2.0mMol, 9:1Z/E isomer mixtures) and 0.208g new penta
20mgAmberlyst 15H are added in the 6mL 2-Me-THF of glycol (2.0mMol) solution+Ion exchange resin, by its in
Stir at room temperature until further conversion is not observed.In CDCl3Pass through in solution1H-NMR measure monitoring conversions.Will be mixed
Compound is filtered by Celite pad, is washed with 2 × 3mL 2-Me-THF, filter vacuum is concentrated.The crude product purity of acquisition is enough
For next step, NMR is determined as the 87 of Z/E isomers:13 mixtures.1H NMR(400MHz,CDCl3)δ：6.57-6.43
(m,1H),5.39-5.27(dd,1H),3.67(s,4H),1.95-1.83(dd,3H),0.97(s,6H)
Step B：Prepare 4x
Using universal method IIc, 4s is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives, 5,5- diformazans
Base -2- [(Z/E) -propyl- 1- alkenyls] -1,3,2- dioxoborinanes (Z/E- mixtures, step A) are as appropriate boric acid
Derivative, obtain and prepare 4x, be the 63 of Z/E isomers:37 mixtures.
1H NMR(500MHz,DMSO-d6)δ：8.95-8.90(s,1H),8.11-8.06(m,1H),8.06-8.01(m,
1H),7.67-7.60(m,1H),7.58-7.52(m,1H),7.52-7.48(m,1H),7.46-7.40(m,1H),7.36-7.29
(m,1H),6.45-5.90(m,1H),6.10-6.04(m,1H),2.06-1.72(dd,3H)
HRMS C19H13ClN2S calculated values：336.0488；Measured value：337.0541(M+H)
Prepare 4y：4- chloro -6- isopropenyls -5- (1- naphthyls) thieno [2,3-d] pyrimidine
Using universal method IIc, 4s is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives, 2- isopropyl alkene
Base -4,4,5,5- tetramethyls -1,3,2- dioxaborolanes obtain as appropriate boronic acid derivatives and prepare 4y.
1H NMR(500MHz,DMSO-d6)δ：8.83(s,1H),7.96(d,1H),7.92(d,1H),7.55-7.37(m,
5H),5.23(m,1H),5.12(m,1H),1.65(dd,3H)
HRMS C19H13ClN2S calculated values：336.0488；Measured value 337.0551 (M+H)
Prepare 4z：4- chloros -5- (1- naphthyls) -6- [(E) -propyl- 1- alkenyls] thieno [2,3-d] pyrimidine
Step A：5,5- dimethyl -2- [(E) -propyl- 1- alkenyls] -1,3,2- dioxoborinanes
To 0.172g (E) -propyl- 1- alkene -1- ylboronic acids (2.0mMol) and the 6mL of 0.208g neopentyl glycols (2.0mMol)
20mg Amberlyst 15H are added in 2-Me-THF solution+Ion exchange resin, it is stirred until not seeing at room temperature
Observe further conversion.In CDCl3Pass through in solution1H-NMR measure monitoring conversions.Mixture is filtered by Celite pad,
Washed with 2 × 3mL2-Me-THF, filter vacuum is concentrated.The purity of the crude product of acquisition is enough to be used in next step.It only contains
E- stereoisomers.1H NMR(400MHz,CDCl3)δ：6.57(m,1H),5.39(dd,1H),3.63(s,4H),1.83(dd,
3H),0.97(s,6H)
Step B：Prepare 4z
Using universal method IIcIIIb, 4s is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives and 5,
The dioxoborinanes (step A) of 5- dimethyl -2- [(E) -propyl- 1- alkenyls] -1,3,2- as appropriate boronic acid derivatives,
Obtain and prepare 4z.
1H NMR(500MHz,DMSO-d6)δ：8.90(s,1H),8.09(d,1H),8.04(d,1H),7.64(dd,1H),
7.58-7.53(m,1H),7.50(dd,1H),7.44(m,1H),7.34(d,1H),6.45(m,1H),6.10-6.03(m,1H),
1.72(dd,3H)
HRMS C19H13ClN2S calculated values：336.0488；Measured value：337.0550(M+H)
Prepare 5a：(2R) -2- [[5- (3- chloro -2- methylphenyls) the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] ammonia
Base] -3- phenyl-propionics
Using universal method Ib, 4t is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin is as appropriate amino acid derivativges, synthetically prepared 5a.Crude material is used by preparative Reverse phase chromatography
0.1%TFA solution and acetonitrile obtain as eluent and prepare 5a, be the 1 of diastereoisomer:1 mixture.
1H NMR(500MHz,DMSO-d6)δ:13.15(br s,1H),8.42-8.41(s,1H),7.62-7.54(d,
1H),7.39-7.17(t,1H),7.21-7.01(m,d,1H),7.21(m,4H),6.82-6.79(d,1H),5.15-5.11(d,
1H),4.82-4.76(q,1H),3.23-3.14(dd,1H),2.73-2.67(dd,1H),2.02-1.80(s,3H)
HRMS C22H17N2O2SClI calculated values：548.9775；Measured value：549.9842 with 549.9864 (M+H)
Prepare 5b：(2R)-2-[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl]
Phenyl] the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] amino] -3- [2- [(2- methylpyrazole -3- bases) methoxyl group] phenyl] third
Acid
Using universal method Ib, 4a is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A1
As appropriate amino acid derivativges, then purified by HILIC, obtain and prepare 5b, the diastereoisomer eluted after being.
MS：(M+H)=802.0
Prepare 5c：(2R) -2- [[5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -
The iodo- thienos of 6- [2,3-d] pyrimidine-4-yl] amino] -3- [2- [(2- ethylpyrazol -3- bases) methoxyl group] phenyl] propionic acid
Using universal method Ib, 4a is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A7
As appropriate amino acid derivativges, purified by HILIC, obtain and prepare 5c, the diastereoisomer eluted afterwards.MS：(M+H)
=816.0
Prepare 6a：(2R) -2- [[the bromo- 6- of 5- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxyls
Base phenyl) propionic acid
Using universal method Ib, 2b is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- hydroxy phenyls) propionic acid obtains as appropriate amino acid derivativges and prepares 6a, be isolated by filtration.
1H NMR(400MHz,DMSO-d6)δ:12.90(br s,1H),9.65(br s,1H),8.41(s,1H),7.70
(m,2H),7.45-7.34(m,3H),7.18(dd,1H),7.04(td,1H),6.80(d,1H),6.72(t,1H),4.96(m,
1H),3.31(dd,1H),3.08(dd,1H)
MS(M+H)：488.0
Prepare 6b：(2R) -3- (2- hydroxy phenyls) -2- [(iodo- 6- propyl-s 1- alkynyls of 5--thieno [2,3-d] pyrimidine -4-
Base) amino] propionic acid
Using universal method Ib, 2c is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- hydroxy phenyls) propionic acid obtains as appropriate amino acid derivativges and prepares 6b.The product passes through filtering rather than color
Spectrometry separates.MS：(M+H)=480.0
Prepare 6c：(2R) -2- [(the iodo- thienos of 6- ethyls -5- [2,3-d] pyrimidine-4-yl) amino] -3- phenyl-propionics
Methyl esters
3.246g is prepared to 2a (10mMol), 3.70g [(1R) -1- benzyl -2- methoxyl group -2- oxo-ethyls] chlorination
The Cs of ammonium (17mMol) and 13.03g2CO3(40mMol) is dissolved in 15mL DMSO, stirs at room temperature, in nitrogen environment until not having
Have and observe further conversion.Then mixture is acidified to pH=1 using 2M HCl solutions, extracted with 2 × 300mL EtOAc
Take.The organic phase NaHCO of merging3Solution washs, dried over sodium sulfate, filtering, is concentrated under reduced pressure.Crude material passes through quick color
Spectrum purifying, using heptane and EtOAc as eluent, obtain and prepare 6c.
1H NMR(500MHz,DMSO-d6)δ：8.39(s,1H),7.33(d,1H),7.30(m,2H),7.25-7.22(m,
3H),5.11(m,1H),3.69(s,3H),3.33(dd,1H),3.18(dd,1H),2.82(q,2H),1.23(t,3H)
HRMS C18H18IN3O2S calculated values：467.0164；Measured value：468.0242(M+H)
Prepare 7a：(2R) -2- [[5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -
6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) ethyl propionate
Step A：(2R) -2- [[5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6-
(4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid
Using universal method IId, 6a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, B4 is prepared and makees
For appropriate boronic acid derivatives, (2R) -2- [[5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethoxies are obtained
Base] phenyl] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid.HRMS
C35H35ClFN5O4S calculated values：675.2082；Measured value：676.2097(M+H)
Step B：Prepare 7a
By 2.3g (2R) -2- [[5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6-
(4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid (3.4mMol) is dissolved in 20mL's
In 1.25M HCl EtOH solution, it is stirred overnight in 40 DEG C.Then by mixture NaHCO3Solution dilutes, and is extracted with DCM.
The organic phase of merging is dried over sodium sulfate, filters, and is concentrated in vacuo.Crude material is by purification by flash chromatography, using DCM and MeOH
As eluent, obtain and prepare 7a.HRMS C37H39ClFN5O4S calculated values：703.2395；Measured value：704.2417(M+H)
Prepare 7ad2：(2R)-2-[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethoxies
Base] phenyl] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) ethyl propionate
Step A：(2R)-2-[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid
Using universal method IId, 6a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, B4 is prepared and makees
For appropriate boronic acid derivatives, (2R) -2- [[5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethoxies are obtained
Base] phenyl] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid is diastereomeric
The mixture of isomers.Mixture is separated by flash chromatography, using HILIC as eluent.The diastereomeric more early eluted
Isomers is collected as preparing 7a1.MS (M+H)：676.2
The diastereoisomer eluted afterwards is collected as preparing 7a2.MS(M+H)：676.2
Step B：Prepare 7ad2
Prepared by 44.51g into 7a2 (6.67mMol) to be dissolved in 85mL 1.25M HCl EtOH solution, it is stirred in 40 DEG C
Night.Then mixture is used into NaHCO3Solution carefully dilutes, and is extracted with DCM.The organic phase of merging is dried over sodium sulfate, mistake
Filter, it is concentrated in vacuo.Crude material, using DCM and MeOH as eluent, is obtained by purification by flash chromatography and prepares 7ad2.
1H NMR(500MHz,DMSO-d6)δ：9.49(s,1H),8.40(s,1H),7.34(d,1H),7.27-7.21(m,
3H),7.20-7.14(m,2H),7.00(td,1H),6.71(dd,1H),6.60(td,1H),6.39(dd,1H),5.03(d,
1H),4.92(m,1H),4.26(t,2H),4.03(m,2H),3.03(dd,1H),2.78(t,2H),2.54(br,4H),2.36
(dd,1H),2.30(br,4H),2.12(s,3H),1.83(s,3H),1.10(t,3H)
HRMS C37H39ClFN5O4S calculated values：703.2395；Measured value：704.2450(M+H)
Prepare 7b：(2R)-2-[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl]
Phenyl] -6- propyl-s 1- alkynyls-thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) ethyl propionate
Step A：(2R)-2-[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base] -6- propyl-s 1- alkynyls-thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid
Using universal method IIb, 6b is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, B4 is prepared and makees
For appropriate boronic acid derivatives, Ataphos is as catalyst, THF:Water 3:1 is used as solvent, obtains diastereoisomer mixing
Thing.They are separated by flash chromatography, using HILIC as eluent.The diastereoisomer eluted afterwards is collected as (2R) -2-
[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6- propyl-s 1- alkynyls-thiophene
And [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid.MS：(M+H)：620.2
Step B：Prepare 7b
By 2.3g (2R) -2- [[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl]
Phenyl] -6- propyl-s 1- alkynyls-thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid (3.71mMol) is molten
In 20mL 1.25M HCl EtOH solution, it is stirred overnight in 40 DEG C.Then by mixture NaHCO3Solution dilutes, and uses
DCM is extracted.The organic phase of merging is dried over sodium sulfate, filters, and is concentrated in vacuo.Crude material is used by purification by flash chromatography
EtOAc or DCM and MeOH is obtained as eluent and is prepared 7b.
1H NMR(500MHz,DMSO-d6)δ：9.47(s,1H),8.41(s,1H),7.21(s,1H),7.21(s,1H),
7.00(td,1H),6.70(dd,1H),6.60(td,1H),6.34(d,1H),5.11(d,1H),4.89(m,1H),4.27(t,
2H),4.03(m,2H),3.06(dd,1H),2.79(t,2H),2.55(br,4H),2.40(dd,1H),2.30(br,4H),
2.12(s,3H),2.00(s,3H),1.97(s,3H),1.11(t,3H)
HRMS C34H38ClN5O4S calculated values：647.2333；Measured value：648.2385(M+H)
Prepare 7c：(2R) -2- [[5- [3- chloros -4- (2- dimethyl aminoethyls epoxide) -2- methylphenyls] -6- propyl-s
1- alkynyls-thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) ethyl propionate
Step A：(2R)-2-[[(5Sa) -5- [3- chloros -4- (2- dimethyl aminoethyls epoxide) -2- methylphenyls] -
6- propyl-s 1- alkynyls-thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid
Using universal method IId, 6b is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, B5 is prepared and makees
For appropriate boronic acid derivatives, non-enantiomer mixture is obtained.They are separated by flash chromatography, using HILIC conducts
Eluent.The diastereoisomer eluted afterwards is collected as (2R) -2- [[(5Sa) -5- [3- chloros -4- (2- dimethyl aminoethyls
Epoxide) -2- methylphenyls] -6- propyl-s 1- alkynyls-thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) third
Acid.MS(M+H)：565.2
Step B：Prepare 7c
By 2.3g (2R) -2- [[(5Sa) -5- [3- chloros -4- (2- dimethyl aminoethyls epoxide) -2- methyl-benzene
Base] -6- propyl-s 1- alkynyls-thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid (4.07mMol) is dissolved in
In 20mL 1.25M HCl EtOH solution, it is stirred overnight in 40 DEG C.Then by mixture NaHCO3Solution dilutes, and uses DCM
Extraction.The organic phase of merging is dried over sodium sulfate, filters, and is concentrated in vacuo.Crude material is by purification by flash chromatography, using DCM
With MeOH as eluent, obtain and prepare 7c.
1H NMR(500MHz,DMSO-d6)δ：9.45(s,1H),8.41(s,1H),7.21(s,1H),7.21(s,1H),
7.00(td,1H),6.70(dd,1H),6.60(td,1H),6.34(d,1H),5.12(d,1H),4.89(m,1H),4.26(m,
2H),4.03(m,2H),3.06(dd,1H),2.74(t,2H),2.39(dd,1H),2.27(s,6H),2.01(s,3H),1.97
(s,3H),1.11(t,3H)
HRMS C31H33ClN4O4S calculated values：592.1911；Measured value：593.1954(M+H)
Prepare 7d：(2R) -2- [[the bromo- 6- of 5- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxyls
Base phenyl) ethyl propionate
2.5g is prepared into the EtOH solution that 6a (5.1mMol) is dissolved in 20mL 1.25M HCl, is stirred overnight in 40 DEG C.It will obtain
The mixture aq.NaHCO obtained3Solution dilutes, and is extracted with DCM.The organic phase of merging is dried over sodium sulfate, filtering, and vacuum is dense
Contracting.Crude material, using heptane and EtOAc as eluent, is obtained by purification by flash chromatography and prepares 7d.1H NMR
(400MHz,DMSO-d6)δ：9.67(s,1H),8.42(s,1H),7.70(m,2H),7.43-7.37(m,3H),7.14(dd,
1H),7.05(td,1H),6.80(dd,1H),6.72(td,1H),5.01(m,1H),4.12(q,2H),3.26(dd,1H),
3.14(dd,1H),1.17(t,3H)
Prepare 7e：(2R) -2- [[6- ethyls -5- (4- hydroxy-2-methyls-phenyl) thieno [2,3-d] pyrimidine-4-yl]
Amino] -3- phenyl-methyl propionates
934mg is prepared into 6c (2mMol), 903mg and prepares B6 (2.4mMol), 231mg Pd (PPh3)4(0.2mMol)、
662mg Ag2CO3(2.4mMol) and 81 μ L methanol (2mMol) are dissolved in 20mL 2-Me-THF, in 110 DEG C in MW reactors
Stirring is until being not observed further conversion.Mixture is filtered by diatomite, diluted with 100mL EtOAc, then
2.5mL TBAF (1M THF solution) are added, mixture is stirred until further conversion is not observed at room temperature.So
Afterwards by mixture NH4Cl solution and salt water washing, it is dried over sodium sulfate, filter, concentration, by purification by flash chromatography, use
Heptane and EtOAc obtain as eluent and prepare 7e, be the mixture of diastereoisomer.
1H NMR(400MHz,CDCl3)δ：8.43-8.43(s,1H),7.26-6.80(m,7H),6.76-6.64(m,2H),
5.18(m,1H),5.03(m,1H),3.66-3.65(s,3H),3.16-3.13(dd,1H),2.73(dd,1H),2.57(m,
2H),2.07-1.80(s,3H),1.18-1.17(t,3H)
MS(M+H)：448.2
Prepare 7f：(2R) -2- [[5- (3,5- dichloro-s -4- hydroxy-2-methyls-phenyl) -6- ethyl-thiophens simultaneously [2,3-
D] pyrimidine-4-yl] amino] -3- phenyl-methyl propionates
402mg is prepared into 7e (0.898mMol) and 300mg NCS (2.245mMol) are dissolved in 5mLTHF, it is straight in 60 DEG C of stirrings
To further conversion is not observed.Be removed in vacuum volatile matter, residue by purification by flash chromatography, using heptane and
EtOAc obtains target product, is the mixture of diastereoisomer as eluent.
1H NMR(500MHz,DMSO-d6)δ:10.46-10.44(s,1H),8.40-8.38(s,1H),7.29-7.24(s,
1H),7.20(m,3H),6.80-6.78(d,2H),5.09-5.01(d,1H),4.95(m,1H),3.59-3.58(s,3H),
3.15-3.13(dd,1H),2.78-2.61(dd,1H),2.53(q,2H),2.02-1.84(s,3H),1.11(t,3H)
HRMS C25H23Cl2N3O3S calculated values：515.0837；Measured value：516.0908(M+H)
Prepare 7g：[[simultaneously [2,3-d] is phonetic for -6- ethyl-thiophens by 5- (3- chloros -4- hydroxy-2-methyls-phenyl) by (2R) -2-
Pyridine -4- bases] amino] -3- phenyl-methyl propionates
Using universal method IIc, 6c is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, B2 is prepared and makees
For appropriate boronic acid derivatives, obtain and prepare 7g, be the mixture of diastereoisomer.MS(M+H)：482.1
Prepare 7gd1：(2R)-2-[[(5Sa) -6- ethyl-thiophens are simultaneously by -5- (3- chloros -4- hydroxy-2-methyls-phenyl)
[2,3-d] pyrimidine-4-yl] amino] -3- phenyl-methyl propionates
The diastereoisomer for preparing 7g is separated by flash chromatography, using heptane and EtOAc as eluent.After wash
De- diastereoisomer is collected as preparing 7gd1.
1H NMR(500MHz,DMSO-d6)δ:10.53(s,1H),8.36(s,1H),7.23(m,2H),7.20(m,1H),
7.04(d,1H),6.98(d,1H),6.80(m,2H),5.11(d,1H),4.90(m,1H),3.57(s,3H),3.10(dd,
1H),2.63(dd,1H),2.51-2.46(m,2H),1.86(s,3H),1.10(t,3H)
HRMS C25H24ClN3O3S calculated values：481.1227；Measured value：482.1313(M+H)
Prepare 7h：(2R) -2- [[6- ethyls -5- (1H- indoles -4- bases) thieno [2,3-d] pyrimidine-4-yl] amino] -
3- phenyl-propionics
Using universal method Ib, 4v is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- hydroxy phenyls) propionic acid obtains as appropriate amino acid derivativges and prepares 7h, be the mixing of diastereoisomer
Thing.
1H NMR(500MHz,DMSO-d6)δ:12.71-12.59(br s,1H),11.48-11.37(s,1H),8.35-
8.30(s,1H),7.64-7.53(d,1H),7.45-7.39(dd,1H),7.30-7.08(t,1H),7.17-6.33(m,6H),
6.07-6.01(s,1H),5.27(d,1H),4.59/4.50(m,1H),2.98-2.83(dd,1H),2.56(m,2H),2.35-
2.15(dd,1H),1.11-1.09(t,3H)
HRMS C25H22N4O2S calculated values：442.1463；Measured value：443.1529 with 443.1538 (M+H)
Prepare 7i：(2R) -2- [[5- (3- chloro -1H- indoles -4- bases) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine -4-
Base] amino] -3- phenyl-methyl propionates
Step A：(2R) -2- [[6- ethyls -5- (1H- indoles -4- bases) thieno [2,3-d] pyrimidine-4-yl] amino] -3-
Phenyl-methyl propionate
8.87g is prepared into 7h (20mMol) and is dissolved in 60mL MeOH, adds 5.88mL cc.H2SO4(60mMol).Will mixing
Thing stirs 2 hours at room temperature, in nitrogen environment.Then pour the mixture into frozen water, obtain (2R) -2- [[6- ethyls -5-
(1H- indoles -4- bases) thieno [2,3-d] pyrimidine-4-yl] amino] -3- phenyl-methyl propionates are the mixed of diastereoisomer
Compound.
1H NMR(400MHz,DMSO-d6)δ:11.52-11.43(s,1H),8.39-8.34(s,1H),7.65-7.57(d,
1H),7.47-7.42(t,1H),7.30-7.11(dd,1H),7.18-6.79(m,2H),7.02(m,1H),6.93(m,1H),
6.65(m,1H),6.34(m,1H),6.05(dt,1H),5.28(m,1H),4.71-4.62(m,1H),3.55-3.41(s,3H),
2.91-2.77(dd,1H),2.57(m,2H),2.37-2.23(dd,1H),1.11-1.10(t,3H)
MS(M+H)：457.2 and 457.2
Step B：Prepare 7i
By 8.477g (2R) -2- [[6- ethyls -5- (1H- indoles -4- bases) thieno [2,3-d] pyrimidine-4-yl] ammonia
Base] -3- phenyl-methyl propionates (18.5mMol), 2.47g NCS (18.5mMol) and 30mL abs.THF stir directly at room temperature
To further conversion is not observed.Then frozen water is poured the mixture into, is extracted with EtOAc.The organic phase of merging is through sulfuric acid
Sodium is dried, and filtering, is concentrated under reduced pressure.Crude material, using heptane and EtOAc as eluent, is obtained by purification by flash chromatography
7i is prepared, is the mixture of diastereoisomer.
1H NMR(500MHz,DMSO-d6)δ:11.73-11.65(d,1H),8.35-8.31(s,1H),7.63-7.56(d,
1H),7.62-7.54(d,1H),7.44-7.15(dd,1H),7.20-7.03(m,3H),7.04-6.84(d,1H),6.70-
6.44(dm,2H),5.09-4.98(d,1H),4.80-4.72(m,1H),3.51-3.38(s,3H),2.93-2.81(dd,1H),
2.52(m,2H),2.46-2.29(dd,1H),1.10-1.09(t,3H)
HRMS C26H23ClN4O2S calculated values：490.1230；Measured value：491.1282 with 491.1316 (M+H)
Prepare 7j：4- chloros -5- (3- chloro -1H- indoles -4- bases) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine
1.099g is prepared into 4v (3.5mMol) and 0.572g NCS (4.2mMol) in 20mL CCl4In mixture in room
The lower stirring of temperature is until being not observed further conversion.Then mixture is poured on trash ice, it is extracted with DCM.Merge
Organic layer it is dried over sodium sulfate, filtering, be concentrated under reduced pressure.Crude material is made by purification by flash chromatography using heptane and EtOAc
For eluent, obtaining 4- chloros -5- (3- chloro -1H- indoles -4- bases) -6- ethyl-thiophens, simultaneously [2,3-d] pyrimidine prepares 7j.1H
NMR(400MHz,CDCl3)δ：8.79(s,1H),8.33(br s,1H),7.47(dd,1H),7.31(t,1H),7.18(d,
1H),7.03(dd,1H),2.73(m,2H),1.24(t,3H)
Prepare 8a：(E) -4- (dimethylamino) -1,1- dimethoxys-butyl- 3- alkene -2- ketone
By 502.1g 1,1- dimethoxy propyl- 2- ketone (4.25mol) and 506.4g 1,1- dimethoxys-N, N- diformazan
Base-methylamine (4.25mol) mixes in 2L flasks, is stirred 3 hours in 105 DEG C.By distilling the continuous MeOH for removing formation.When
MeOH formed stop (in 65 DEG C of head temperatures) after, by reactant mixture be evaporated in vacuo and (pressure be slowly lowered to 30mbar) with
Remove accessory substance and unreacted raw material.Crude material is distilled in 0.1mbar.Between 107-118 DEG C of head temperature of collection
Component (160-165 DEG C of bath temperature), obtain yellow oil.1H NMR(500MHz,DMSO-d6)δ：7.59(d,1H),5.17(d,
1H),4.42(s,1H),3.25(s,6H),3.09(s,3H),2.78(s,3H)
Prepare 8b：4- (dimethoxy-methyl) -2- methylsulfonyl-pyrimidins
Step A：4- (dimethoxy-methyl) -2- methylsulfanyl pyrimidins
198g sodium methoxides (3.67mMol) are dissolved in 3L MeOH, are cooled to 0 DEG C.322g thiocarbamides are added by several times
(4.23mol), stir the mixture for 1 hour.Then 488g is added dropwise in 0 DEG C and prepares 8a (2.82mol), be then heated to 70
DEG C until further conversion is not observed.Room temperature is cooled to, 237mL methyl iodides (3.81mol), keeping temperature is added dropwise
Less than 28 DEG C, the mixture of acquisition is stirred overnight at room temperature.Filtered, filtrate decompression concentration, diluted, used with EtOAc
Water and salt water washing.The water layer of merging is extracted with EtOAc.The organic layer of merging is dried over sodium sulfate, filtering, is concentrated under reduced pressure.Will
Residue is dissolved in 500mL Et2O, filtered by silicagel pad, using Et2O is as eluent.Filtrate decompression is concentrated, obtained pale yellow
Color grease.1H NMR(400MHz,DMSO-d6)δ：8.69(d,1H),7.23(d,1H),5.22(s,1H),3.33(s,6H),
2.52(s,3H)
Step B：Prepare 8b
In -5 DEG C, to 180g 4- (dimethoxy-methyl) -2- methylsulfanyl pyrimidins (940mMol) in 1.5L methanol
752g is added by several times with the solution in 1.5L water(potassium peroxydisulfate (potassium
Peroxymonosulfate), 1220mMol), then it is stirred overnight in 0 DEG C.Reactant mixture is concentrated under reduced pressure using 30 DEG C of baths
To the volume of half, then mixture is filtered, sediment is washed with DCM.Filtrate is extracted with DCM.The organic layer of merging is through sulphur
Sour magnesium is dried, and filtering, is concentrated under reduced pressure, and obtains light brown grease.1H NMR(400MHz,CDCl3)δ：8.98(d,1H),7.97
(d,1H),5.36(s,1H),3.47(s,6H),3.39(s,3H)
Prepare 9a：(2R) -2- amino -3- (2- hydroxy phenyls) propionate hydrochloride
By 24.6g (2R) -2- amino -3- (2- hydroxy phenyls) propionic acid (136mMol) at room temperature in 900mL 3M
Stirred 40 hours in HCl methanol solution.Reactant mixture is concentrated under reduced pressure, keeps bath temperature to be less than 40 DEG C.By residue second
Ether is ground, and obtains product, for cream-colored glittering powder.HRMS C11H15NO3(free alkali) calculated value：209.1052；Measured value：
210.1128(M+H)
Prepare 9b：(2R) -2- (t-butoxy carbonylamino) -3- (2- hydroxy phenyls) methyl propionate
Prepared by 16.7g into 9a (73.0mMol) to be suspended in 180mL DCM.Add 30.5mL (219mMol) TEA, solution
Cooled down using ice-water bath.Being slowly added to the 75mL DCM solution of the dimethyl dicarbonate butyl esters (73.0mMol) of 15.6g bis-, (2.5 is small
When).Mixture is stirred overnight at room temperature.Then 100mL water is added, organic phase is separated, is washed with water, 1M HCl solutions,
Finally it is washed with water and washs.Organic phase is dried over sodium sulfate, filtering, filtrate decompression is concentrated, obtains the product for grease.
Prepare A1：(2R) -2- amino -3- [2- [(2- methylpyrazole -3- bases) methoxyl group] phenyl] propionic acid
Using universal method IXa, (2- methylpyrazole -3- bases) methanol obtains as appropriate 01 derivatives and prepares A1.MS
(M+H)：276.2
Prepare A2：(2R) -2- amino -3- [2- [(2- ethyoxyls pyrimidine-4-yl) methoxyl group] phenyl] propionic acid
Using universal method IXa, C1 is prepared as appropriate 01 derivatives, obtains and prepares A2.MS(M+H)：318.1
Prepare A3：(2R) -2- amino -3- [2- [(2- butyl pyrazole-3-yl) methoxyl group] phenyl] propionic acid
Using universal method IXa, C2 is prepared as appropriate 01 derivatives, obtains and prepares A3.MS(M+H)：318.2
Prepare A4：(2R) -2- amino -3- [2- [[2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group] phenyl] propionic acid
Using universal method IXa, C3 is prepared as appropriate 01 derivatives, obtains and prepares A4.MS(M+H)：380.2
Prepare A5：(2R) -2- amino -3- [2- (2- pyridinyl methoxies) phenyl] propionic acid
Using universal method IXa, 2- pyridylcarbinols obtain as appropriate 01 derivatives and prepare A5.MS(M+H)：
273.1
Prepare A6：(2R) -2- amino -3- [2- (2,2,2- trifluoro ethoxies) phenyl] propionic acid
Using universal method IXb, 2,2,2- trifluoroethyl triflates are made as appropriate alkylating reagent
Standby A6.MS(M+H)：264.1
Prepare A7：(2R) -2- amino -3- [2- [(2- ethylpyrazol -3- bases) methoxyl group] phenyl] propionic acid
Using universal method IXa, (2- ethylpyrazol -3- bases) methanol obtains as appropriate 01 derivatives and prepares A7.
HRMS C15H19N3O3Calculated value：289.1426, measured value：290.1512(M+H)
Prepare A8：(2R) -2- amino -3- [2- [[2- (2,2,2- trifluoro ethoxies) pyrimidine-4-yl] methoxyl group] phenyl]
Propionic acid
Using universal method IXa, C8 is prepared as appropriate 01 derivatives, obtains and prepares A8.MS(M+H)：372.1
Prepare A9：(2R) -2- amino -3- [2- [2- (dimethylamino) -2- oxo-ethoxvs] phenyl] propionic acid
Using universal method IXb, 2- chloros-DMA is prepared as appropriate alkylating reagent
A9.MS(M+H)：267.1
Prepare A10：(2R) -2- amino -3- [2- (2- cyclopenta ethyoxyl) phenyl] propionic acid
Using universal method IXa, 2- cyclopentyl-ethanols obtain as appropriate 01 derivatives and prepare A10.MS(M+H)：
278.2
Prepare A11：(2R) -2- amino -3- (2- phenethyloxyphenyls) propionate hydrochlorate
Using universal method IXa, 2- phenylethanols obtain as appropriate 01 derivatives and prepare A11.MS(M+H)：
286.1
Prepare A12：(2R) -2- amino -3- [2- (3- phenyl-propoxies) phenyl] propionic acid
Using universal method IXa, 3- phenyl propyl- 1- alcohol obtains as appropriate 01 derivatives and prepares A12.MS(M+H)：
300.2
Prepare A13：(2R) -2- amino -3- [2- [(3- chlorophenyls) methoxyl group] phenyl] propionic acid
Using universal method IXa, (3- chlorophenyls) methanol obtains as appropriate 01 derivatives and prepares A13.MS(M+
H)：306.1
Prepare A14：(2R) -2- amino -3- [2- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] propionic acid
Using universal method IXa, 2- (4- methylpiperazine-1-yls) ethanol as appropriate 01 derivatives, is prepared
A14.MS(M+H)：308.2
Prepare A15：(2R) -2- amino -3- [2- (2- dimethyl aminoethyls epoxide) phenyl] propionic acid
Using universal method IXa, 2- (dimethylamino) ethanol obtains as appropriate 01 derivatives and prepares A15.MS(M
+H)：253.2
Prepare A16：(2R) -2- amino -3- [2- [3- (dimethylamino) propoxyl group] phenyl] propionic acid
Using universal method IXa, 3- (dimethylamino) propyl- 1- alcohol obtains as appropriate 01 derivatives and prepares A16.
MS(M+H)：267.2
Prepare B1：3- methyl -4- (3,3,4,4- tetramethyl-ring pentaborane -1- bases) -1H- indoles
By the bromo- 3- Methyl-1H-indoles (8.9mMol) of 1.87g 4-, double (pinacol conjunction) two boron (19.6mMol) of 5.028g
35mL dry DMFs are dissolved in ar gas environment with 2.65g potassium acetates (26.7mMol), then add 652mg [1,1'- bis- (hexichol
Base phosphino-) ferrocene] palladium chloride (II) (0.89mMol).Reactant mixture is heated to 85 DEG C and stirred until not observing
To further conversion.Then it is concentrated under reduced pressure, by purification by flash chromatography, using heptane and EtOAc as eluent, is obtained
B1 must be prepared.
1H NMR(400MHz,CDCl3)δ：7.92(br s,1H),7.56(d,1H),7.42(dd,1H),7.16(t,1H),
7.01(d,1H),2.47(d,3H),1.40(s,12H)
HRMS C15H20NO2B calculated values：257.1587；Measured value：258.1665(M+H)
Prepare B2：2- chloro -3- methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) phenol
Step A：(the bromo- 2- chloros-phenoxy groups of 4-)-trimethyl-silane
The bromo- 2- chloros of 20.8g 4--phenol (100mMol) is dissolved in the anhydrous THF of 150mL, then adds 24.2g HMDS
(150mMol).Reactant mixture is stirred 1.5 hours in 85 DEG C, ar gas environment, is then concentrated under reduced pressure.The crude product production of acquisition
Thing, which need not be further purified, directly to be used.1HNMR(200MHz,CDCl3)δ：7.49(d,1H),7.23(dd,1H),6.75
(d,1H),0.26(s,9H)
Step B：The bromo- 2- chloros -3- methyl-phenols of 4-
In -78 DEG C, ar gas environment, by 48mLnBuLi solution (120mMol, 2.5M hexane solution) is added dropwise to
In the anhydrous DIPA of 12.1g (120mMol) 250mL anhydrous THF solutions.Mixture is stirred 30 minutes at a temperature of identical,
Then 28.0g (the bromo- 2- chloros-phenoxy groups of 4-)-trimethyl-silane (100mMol) is added dropwise.After 2.5 hours, 21.3g is added dropwise
MeI (150mMol), then removes cryostat, the mixture was stirred overnight.Reactant uses 100mL NH4OH solution and 200mL
NH4Cl solution is quenched, and is then extracted with EtOAc.Organic phase is dried over sodium sulfate, filtering, filtrate decompression is concentrated.By acquisition
Atrament flows back for several times and removed together with pure hexane (150-150mL equal portions), leaves black tar.By the organic phase of merging
It is concentrated under reduced pressure, obtains 19.0g crude materials, it, which need not be further purified, directly to use.1H NMR(200MHz,CDCl3)δ：
7.32(d,1H),6.76(d,1H),5.62(s,1H),2.49(s,3H)
Step C：(the bromo- 2- chloros -3- methyl-phenoxvs of 4-)-trimethyl-silane
20.8g HMDS (129mMol) are added into the bromo- 2- chloros -3- methyl-phenols (86.0mMol) of 19.0g 4-
In 150mL anhydrous THF solutions.Mixture is stirred 1.5 hours in 85 DEG C, ar gas environment, is then concentrated under reduced pressure.The production of acquisition
Thing, which need not be further purified, directly to be used.1H NMR(200MHz,CDCl3)δ：7.30(d,1H),6.63(d,1H),2.50
(s,3H),0.28(s,9H)
Step D：Prepare B2
The 250mL of 25.2g (the bromo- 2- chloros -3- methyl-phenoxvs of 4-)-trimethyl-silane (86.0mMol) is anhydrous
THF solution is cooled to -78 DEG C in ar gas environment, and 38mL is then added dropwisen(94.6mMol, 2.5M hexane are molten for BuLi solution
Liquid).19.2g 2- isopropoxy -4,4,5,5- tetramethyl -1,3,2- dioxaborolanes (103mMol) are added dropwise after 5 minutes.
Cryostat is removed, mixture is slowly heated to room temperature.Then 200mL NH are fed the mixture into4In Cl solution, extracted with EtOAc
Take.The organic layer of merging is concentrated under reduced pressure, filtered by silicagel pad, using hexane and EtOAc as eluent.Crude material exists
Recrystallized in the mixture of EtOAc and hexane, obtain and prepare B2.1H NMR(500MHz,DMSO-d6)δ:10.40(s,1H),
7.42(d,1H),6.80(d,1H),2.49(s,3H),1.27(s,12H)
Prepare B3：[2- chloro -3- methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) benzene
Epoxide]-triisopropyl-silane
Step A：(the bromo- 2- chloros-phenoxy groups of 4-)-triisopropyl-silane
The bromo- 2- chloros of 200g 4--phenol (0.97mol) and 126mL TIPSCl (1.18mol) are dissolved in 1.6L DCM.
167g imidazoles (2.45mol) is added, mixture is stirred at room temperature 2 hours.Then volatiles evaporated in vacuo, residue is molten
In 1.5L EtOAc.It is dried over sodium sulfate by mixture salt water washing, filtering, filtrate decompression is concentrated.Triisopropyl first silicon
Alkyl phosphonium hydroxide impurity is removed by distillation (120 DEG C, 0.01mMHg).Residue is filtered by the short pad of silica gel, Hex,
It is concentrated under reduced pressure.Product (colorless oil), which need not be further purified, is used directly for next step.
1H NMR(400MHz,CDCl3)δ：7.49 (d, 1H), 7.21 (dd, 1H), 6.78 (d, 1H), 1.31 (heptet,
3H),1.14(d,18H)
MS (EI, 70eV) m/z (% relative intensities, [ion])：63(30),79(24),93(41),170(17),235
(19),251(16),265(24),293(23),319(77),321(100),323(28),362(1,[M+])。
Step B：(the bromo- 2- chloros -3- methyl-phenoxvs of 4-)-triisopropyl-silane
The anhydrous DIPA of 76.0mL (0.54mol) are dissolved in the anhydrous THF of 1.2L in ar gas environment, in -78 DEG C of dropwise additions
51.2mL nBuLi solution (0.512mol, 10M hexane solution).Mixture is stirred 45 minutes at a temperature of identical.So
178g (the bromo- 2- chloros-phenoxy groups of 4-)-triisopropyl-silane (0.488mol) is added dropwise after -78 DEG C, white suspension is stirred
Mix until further conversion is not observed.Then 36.5mL MeI (0.586mMol) are added at a temperature of this, reaction is mixed
Compound under further cooling down without being stirred overnight.Volatiles evaporated in vacuo.1.5L EtOAc are dissolved the residue in, are washed with salt
Wash.Organic phase is dried over sodium sulfate, filtering, filtrate decompression is concentrated.Crude material is filtered by short column of silica gel, is made using hexane
For eluent, it is concentrated under reduced pressure, obtains the product for light yellow oil.1H NMR(400MHz,CDCl3)δ：7.30(d,1H),
6.68 (d, 1H), 2.53 (s, 3H), 1.32 (heptet, 3H), 1.14 (d, 18H)
Step C：Prepare B3
By 178g (the bromo- 2- chloros -3- methyl-phenoxvs of 4-)-triisopropyl-silane (0.472mol) in ar gas environment
The anhydrous THF of 1.4L are dissolved in, 52mL is added dropwise in -78 DEG CnBuLi solution (0.52mol, 10M hexane solution).By mixture in this
At a temperature of stir 5 minutes.Then 116mL 2- isopropoxy -4,4,5,5- tetramethyl -1,3,2- dioxaborolanes are added
(0.569mol), mixture is warmed to room temperature.Volatiles evaporated in vacuo.1.5L EtOAc are dissolved the residue in, are washed with salt
Wash.Organic phase is dried over sodium sulfate, filtering, filtrate decompression is concentrated.2- isopropoxy -4,4,5,5- tetramethyls -1,3,2- two
Oxa- ring pentaborane impurity is removed by distillation (80 DEG C, 0.01mMHg).Crude material is ground in MeOH, is obtained as white admittedly
The preparation B3 of body.1H NMR(400MHz,CDCl3)δ：7.53(d,1H),6.74(d,1H),2.60(s,3H),1.34(s,12H),
1.32(m,3H),1.12(d,18H)
Prepare B4:1- [2- [2- chloro -3- methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2-
Base) phenoxy group] ethyl] -4- thyl-piperazins
By 10.0g prepare B2 (37.2mMol), 8.7g 2- (4- methylpiperazine-1-yls) ethanol (60.3mMol) and
15.8g PPh3(60.3mMol) is dissolved in 100mL dry toluenes, be then added dropwise 27mL diethyl azodiformates (60.3mMol,
40% toluene solution).Mixture is stirred until further conversion is not observed in 50 DEG C, ar gas environment.Decompression
Evaporating volatile substances, add 100mL Et2O.The white crystals of precipitation are filtered, use Et2O is washed.Filtrate decompression is concentrated, by fast
Fast chromatogram purification, using CHCl3With MeOH as eluent.The light brown grease of acquisition is crystallized in hexane, is
The preparation B4 of pale solid.1H NMR(500MHz,DMSO-d6)δ：7.56(d,1H),6.99(d,1H),4.15(t,2H),
2.72(t,2H),2.51(s,3H),2.50(br s,4H),2.29(br s,4H),2.13(s,3H),1.29(s,12H)
Prepare B5:1- [2- [2- chloro -3- methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2-
Base) phenoxy group] ethyl] -4- thyl-piperazins
10.0g is prepared into B2 (37.2mMol), 5.366g N, N- dimethylethanolamines (60.3mMol) and 15.8g PPh3
(60.3mMol) is dissolved in 100mL dry toluenes, and 27mL diethyl azodiformate (60.3mMol, 40% toluene is then added dropwise
Solution).Mixture is stirred until further conversion is not observed in 50 DEG C, ar gas environment.Volatiles evaporated in vacuo,
Add 100mL Et2O.The white crystals of precipitation are filtered, use Et2O is washed.Filtrate decompression is concentrated, it is pure by flash chromatography
Change, using CHCl3With MeOH as eluent.The light brown grease of acquisition is crystallized in hexane, obtains and prepares B5.1H
NMR(400MHz,DMSO-d6)δ：7.56(d,1H),6.99(d,1H),4.13(t,2H),2.66(t,2H),2.51(s,3H),
2.23(s,6H),1.29(s,12H)
Prepare B6：[4- (5,5- dimethyl -1,3,2- dioxoborinane -2- bases) -3- methyl-phenoxvs]-three
Isopropyl-silane
Step A：4- (5,5- dimethyl -1,3,2- dioxoborinane -2- bases) -3- methyl-phenols
By 4.675g (4- hydroxy-2-methyls-phenyl) boric acid (30.76mMol), 3.204 neopentyl glycols (32.9mMol),
Amberlyst 15H+Stirred at room temperature, in nitrogen environment with 150mL 2-Me-THF until further turn is not observed
Change.Then mixture is filtered by diatomite, filtrate decompression is concentrated, obtain 4- (5,5- dimethyl -1,3,2- dioxa boron
Azacyclohexane -2- bases) -3- methyl-phenols.1H NMR(400MHz,CDCl3)δ：7.64(m,1H),6.60(m,2H),5.23(br
s,1H),3.75(s,4H),2.47(s,3H),1.01(s,6H)
Step B：Prepare B6
By 30.76mMol 4- (5,5- dimethyl -1,3,2- dioxoborinane -2- bases) -3- methyl-phenols,
8.56mL TIPSCl (40mMol) and 4.19g imidazoles (61.52mMol) is dissolved in 100mL DCM, at room temperature, in nitrogen environment
Stirring is until being not observed further conversion.Imidazole hydrochloride is filtered to remove, filtrate decompression is concentrated, passes through quick color
Spectrum purifying, using heptane and EtOAc as eluent, obtain and prepare B6.1H NMR(400MHz,CDCl3)δ：7.62(d,1H),
6.68-6.66(m,2H),3.76(s,4H),2.47(s,3H),1.32-1.21(m,3H),1.11(d,18H),1.03(s,6H)
Prepare B7：2- (the bromo- 2- methylphenyls of 3-) -4,4,5,5- tetramethyl -1,3,2- dioxaborolanes
By 2.362g 2, the bromo- toluene (9.45mMol) of 6- bis- is dissolved in the anhydrous THF of 10mL in nitrogen environment, by mixture
It is cooled to -78 DEG C.Then 5.2mL nBuLi (2.0M pentane solution, 10.4mMol) is added dropwise, stirs the mixture for 15 minutes.
Then 2.31mL 2- isopropoxies -4,4 are added dropwise, 5,5- tetramethyls -1,3,2- dioxaborolanes (11.3mMol) will be mixed
Compound warms to room temperature.It is stirred for until further conversion is not observed.Then mixture uses NH4The Cl aqueous solution is rapid
It is cold, extracted with EtOAc.The organic layer of merging is dried over sodium sulfate, filtering, filtrate decompression is concentrated.Crude material passes through quick
Chromatogram purification, using heptane and EtOAc as eluent, obtain and prepare B7.1H NMR(400MHz,CDCl3)δ：7.67(d,
1H),7.62(d,1H),7.10(t,1H),2.53(s,3H),1.29(s,12H)
Prepare C1：(2- ethyoxyls pyrimidine-4-yl) methanol
Step A：4- (dimethoxy-methyl) -2- ethyoxyls-pyrimidine
1500mg is prepared into 8b (6.46mMol) and is dissolved in 60mL ethanol, then adds 527mg caustic alcohols (7.75mMol), will
Mixture stirs 1 hour at room temperature.Volatiles evaporated in vacuo, residue is by purification by flash chromatography, using heptane and EtOAc
As eluent, 4- (dimethoxy-methyl) -2- ethyoxyls-pyrimidine is obtained.MS(M+H):199.2
Step B：Prepare C1
Using universal method Va, 4- (dimethoxy-methyl) -2- ethyoxyls-pyrimidine is prepared as appropriate acetal
C1。MS(M+H):155.2
Prepare C2：(1- butyl -1H- pyrazoles -5- bases) methanol
Using universal method Vb, 1- butyl pyrazoles obtains as appropriate alkyl pyrazole and prepares C2.
1H NMR(400MHz,DMSO-d6)δ：7.30(d,1H),6.12(d,1H),5.23(t,1H),4.49(d,2H),
4.06(t,2H),1.72(m,2H),1.26(m,2H),0.88(t,3H)
MS(M+H):155.2
Prepare C3：[2- (2- methoxyphenyls) pyrimidine-4-yl] methanol
Step A：4- (dimethoxy-methyl) -2- (2- methoxyphenyls) pyrimidine
Using universal method Vc, 2- methoxybenzenes formamidine acetate obtains 4- (dimethoxy first as appropriate amidine salt
Base) -2- (2- methoxyphenyls) pyrimidine.1H NMR(400MHz,DMSO-d6)δ：8.93(d,1H),7.55-7.44(m,3H),
7.16(d,1H),7.06(m,1H),5.31(s,1H),3.76(s,3H),3.37(s,6H)
Step B：Prepare C3
261mg 4- (dimethoxy-methyl) -2- (2- methoxyphenyls) pyrimidines (1.0mMol) are dissolved in 2mL HCl's
Dioxane solution (4M solution), 2mL water is then added, mixture is stirred 16 hours in 50 DEG C.Reactant mixture is cooled down
To 0 DEG C, 320mg NaOH (8.0mMol) are then added by several times.Using 10%K2CO3Solution adjusts pH to 8, then adds
76mg sodium borohydrides (2.0mMol), mixture is stirred 30 minutes in 0 DEG C.Reactant mixture is diluted with 5mL water, uses EtOAc
Extraction.The organic phase of merging is dried over sodium sulfate, filtering, filtrate decompression is concentrated.Crude material is adopted by purification by flash chromatography
By the use of heptane and EtOAc as eluent, obtain and prepare C3.1H NMR(400MHz,DMSO-d6)δ：8.84(d,1H),7.50-
7.42(m,3H),7.14(d,1H),7.03(m,1H),5.66(t,1H),4.58(d,2H),3.75(s,3H)
Prepare C4：(1- tert-butyl -1H- pyrazoles -5- bases) methanol
Step A:1- tert-butyls -5- (dimethoxy-methyl) -1H- pyrazoles
Using universal method Vd, tert-butyl hydrazine hydrochloride obtains 1- tert-butyls -5- (two as appropriate hydrazine hydrochloride
Methoxy) -1H- pyrazoles.1H NMR(400MHz,DMSO-d6)δ：7.34(d,1H),6.34(d,1H),5.74(s,1H),
3.24(s,6H),1.57(s,9H)
Pay attention to：Also 1- tert-butyls -3- (dimethoxy-methyl) -1H- pyrazoles is obtained.1H NMR(400MHz,DMSO-d6)δ：
7.75(d,1H),6.18(d,1H),5.34(s,1H),3.24(s,6H),1.50(s,9H)
Step B：Prepare C4
Using universal method Ve, 1- tert-butyls -5- (dimethoxy-methyl) -1H- pyrazoles obtains as appropriate acetal
Prepare C4.1H NMR(400MHz,DMSO-d6)δ：7.27(d,1H),6.19(d,1H),5.31(t,1H),4.61(d,2H),
1.56(s,9H)
Prepare C5：[2- (2- methoxy ethyls) pyrimidine-4-yl] methanol
Step A：4- (dimethoxy-methyl) -2- (2- methoxy ethyls) pyrimidine
Using universal method Vc, 3- methoxy propyl amidine hydrochlorides obtain 4- (dimethoxy first as appropriate amidine hydrochloride
Base) -2- (2- methoxy ethyls) pyrimidine.1H NMR(400MHz,DMSO-d6)δ：8.78(d,1H),7.38(d,1H),5.25(s,
1H),3.80(t,2H),3.33(s,6H),3.22(s,3H),3.11(t,2H)
Pay attention to：Also 2- [4- (dimethoxy-methyl) pyrimidine -2-base]-N, N- dimethyl-ethylamines are obtained.MS(M+H)：
226.2
Step B：Prepare C5
Using universal method Va, 4- (dimethoxy-methyl) -2- (2- methoxy ethyls) pyrimidine as appropriate acetal, obtains
C5 must be prepared.1H NMR(400MHz,DMSO-d6)δ：8.70(d,1H),7.39(d,1H),5.60(t,1H),4.52(d,2H),
3.78(t,2H),3.22(s,3H),3.06(t,2H)
Prepare C6：[1- (2,2,2- trifluoroethyls) -1H- pyrazoles -5- bases] methanol
Step A：5- (dimethoxy-methyl) -1- (2,2,2- trifluoroethyls) -4,5- dihydro-1 h-pyrazole -5- alcohol
Using universal method Vd, in the absence of sodium methoxide, methanol, 2,2,2- trifluoroethyl hydrazines are substituted using ethanol
(the 70w/w% aqueous solution) obtains 5- (dimethoxy-methyl) -1- (2,2,2- trifluoroethyl) -4,5- bis- as appropriate hydrazine
Hydrogen -1H- pyrazoles -5- alcohol.1H NMR(400MHz,DMSO-d6)δ：6.83(t,1H),6.03(s,1H),4.30(s,1H),3.95
(m,1H),3.47(m,1H),3.40(d,6H),2.88(m,1H),2.50(m,1H)
Step B：Prepare C6
Using universal method Ve, 5- (dimethoxy-methyl) -1- (2,2,2- trifluoroethyl) -4,5- dihydro-1 h-pyrazoles -
5- alcohol obtains as appropriate acetal and prepares C6.1H NMR(400MHz,DMSO-d6)δ：7.48(d,1H),6.27(d,1H),
5.46(t,1H),5.08(q,2H),4.56(d,2H)
Prepare C7：(2- (morpholine -4- bases) pyrimidine-4-yl) methanol
Step A：4- [4- (dimethoxy-methyl) pyrimidine -2-base] morpholine
25.0g is prepared into 8b (107.6mMol) and is dissolved in 161mL morpholines, mixture is stirred until not seeing at room temperature
Observe further conversion.Then it is concentrated under reduced pressure, crude material is made by purification by flash chromatography using heptane and EtOAc
For eluent, 4- [4- (dimethoxy-methyl) pyrimidine -2-base] morpholine is obtained.
Step B：Prepare C7
Using universal method Va, 4- [4- (dimethoxy-methyl) pyrimidine -2-base] morpholines are prepared as appropriate acetal
C7。1H NMR(400MHz,DMSO-d6)δ：8.35(d,1H),6.75(dm,1H),5.431(t,1H),4.36(dm,2H),3.67
(m,4H),3.63(m,4H)
Prepare C8：[2- (2,2,2- trifluoro ethoxies) pyrimidine-4-yl] methanol
Step A：4- (dimethoxy-methyl) -2- (2,2,2- trifluoro ethoxies) pyrimidine
5.00g is prepared into 8b (21.5mMol) and is dissolved in 54mL anhydrous acetonitriles, then adds 5.95g K2CO3(43.1mMol)
With the trifluoroethanols (32.3mMol) of 3.24g 2,2,2-, mixture is further turned in 60 DEG C of stirrings until being not observed
Change.Reactant mixture is cooled down, filtered, solid is washed with EtOAc, then concentrates filtrate decompression.Crude material passes through quick
Chromatogram purification, using heptane and EtOAc as eluent, obtain 4- (dimethoxy-methyl) -2- (2,2,2- trifluoro ethoxy)
Pyrimidine.1H NMR(400MHz,DMSO-d6)δ：8.74(d,1H),7.32(d,1H),5.25(s,1H),5.05(q,2H),3.34
(s,6H)
Step B：Prepare C8
Using universal method Va, 4- (dimethoxy-methyl) -2- (2,2,2- trifluoro ethoxy) pyrimidine is as appropriate contracting
Aldehyde, obtain and prepare C8.1H NMR(400MHz,DMSO-d6)δ：8.65(d,1H),7.32(d,1H),5.69(t,1H),5.02(q,
2H),4.51(d,2H)
Prepare C9：[2- (2- fluorophenyls) pyrimidine-4-yl] methanol
Step A：The fluoro- N'- hydroxy-benzamidines of 2-
By 11.48g hydroxylamine hydrochlorides (165mMol), 13.87g NaHCO3(165mMol) and 120mL MeOH mixture
Stir 30 minutes at room temperature.Then 10g 2- fluorobenzonitriles (82.6mMol) are added, by mixture in 75 DEG C of stirrings until not having
It was observed that further conversion.Partial solvent is evaporated under reduced pressure, filtered residue, is washed with MeOH.Filtrate decompression is concentrated, then
It is diluted with water, is extracted with EtOAc.The organic phase of merging is dried over sodium sulfate, filtering, filtrate decompression is concentrated, and it is fluoro- to obtain 2-
N'- hydroxy-benzamidines.
Step B：2- fluorobenzene carbonamidines
The fluoro- N'- hydroxy-benzamidines (81.55mMol) of 12.67g 2- are dissolved in 300mL AcOH in 0 DEG C, add 9.24mL
Ac2O(97.86mMol).Mixture is stirred until further conversion is not observed at room temperature.Then 630mg is added
10%Pd/C, by mixture, (4bars) is stirred until further conversion is not observed in the hydrogen gas atmosphere.Mixture is led to
Diatomite filtering is crossed, filtrate decompression is concentrated, obtains 2- fluorobenzene formamidine acetates.MS (M (free alkali)+H):139.4
Step C：4- (dimethoxy-methyl) -2- (2- fluorophenyls) pyrimidine
Using universal method Vc, 2- fluorobenzene carbonamidine obtains 4- (dimethoxy-methyl) -2- (2- fluorobenzene as appropriate amidine
Base) pyrimidine.MS(M+H)：249.2
Step D：Prepare C9
Using universal method Va, 4- (dimethoxy-methyl) -2- (2- fluorophenyls) pyrimidine as appropriate acetal, is made
Standby C9.MS(M+H)：205.2
Prepare C10：[2- [2- (2- methoxy ethoxies) phenyl] pyrimidine-4-yl] methanol
Step A：N'- hydroxyls -2- methoxy ethoxies-benzenecarboximidamide
2eq. hydroxylamine hydrochlorides are dissolved in MeOH (1mL/mmol), then add 2eq.NaHCO3.By mixture at room temperature
Stirring 20 minutes, 1eq.2- methoxy ethoxies-benzonitrile is then added, mixture backflow is further until being not observed
Conversion.Evaporation section MeOH, residue filtering, filtrate decompression is concentrated.N'- hydroxyls-the 2- (2- methoxy ethoxies) of acquisition
Benzenecarboximidamide, which need not be further purified, directly to be used.1H NMR(400MHz,CDCl3)δ：9.48(s,1H),7.45(m,1H),
7.34(m,1H),7.08(d,1H),6.94(td,1H),5.65(br s,2H),4.17(m,2H),3.67(m,2H),3.31(s,
3H)
MS(M+H)：211.2
Step B：2- methoxy ethoxies-benzenecarboximidamide
8.22g N'- hydroxyls -2- (2- methoxy ethoxies) benzenecarboximidamides (39.1mMol) are dissolved in 80mL AcOH in 0 DEG C,
Then 4.43mL Ac are added dropwise2O(46.92mMol).Mixture is stirred at room temperature until further turn is not observed
Change.575mg 10%Pd/C are added, (4bars) stirring further turns until being not observed in the hydrogen gas atmosphere by mixture
Change.Mixture is filtered by diatomite, filtrate decompression is concentrated, obtains 2- (2- methoxy ethoxies) benzenecarboximidamide acetate.
MS(M+H):195.2
Step C：4- (dimethoxy-methyl) -2- [2- methoxy ethoxies-phenyl] pyrimidine
Using universal method Vc, 2- (2- methoxy ethoxies) benzenecarboximidamide acetates obtain 4- (two as appropriate amidine salt
Methoxy) -2- [2- methoxy ethoxies-phenyl] pyrimidine.
1H NMR(400MHz,CDCl3)δ：8.92(d,1H),7.55(m,1H),7.47(m,1H),7.45(m,1H),7.17
(d,1H),7.08(m,1H),5.29(s,1H),4.12(m,2H),3.57(m,2H),3.36(s,6H),3.20(s,3H)
MS(M+H)：305.0
Step D：Prepare C10
Using universal method Va, 4- (dimethoxy-methyl) -2- [2- methoxy ethoxies-phenyl] pyrimidines are as appropriate
Acetal, obtain and prepare C10.
1H NMR(400MHz,CDCl3)δ：8.84(d,1H),7.53(m,1H),7.47(m,1H),7.43(m,1H),7.14
(d,1H),7.05(td,1H),5.64(t,1H),4.58(d,2H),4.11(m,2H),3.57(m,2H),3.21(s,3H)
MS(M+H)：261.0
Embodiment 1：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -
6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine
With
Embodiment 2：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -
6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine
Using universal method VI, prepare 7a and then hydrolyze root as appropriate alcohol as appropriate phenol derivatives, methanol
The intermediate formed according to universal method VII, embodiment 1 is obtained, for the diastereoisomer more early eluted.HRMS
C36H37ClFN5O4S calculated values：689.2240, measured value：345.6182(M+2H)
Obtain embodiment 2, the diastereoisomer eluted after being.HRMS C36H37ClFN5O4S calculated values：689.2240
Measured value：345.6185(M+2H)
Embodiment 3：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -
6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- [(1- methyl isophthalic acid H- pyrazoles -5- bases) methoxyl group]-D- phenylpropyl alcohol ammonia
Acid
Using universal method VI, 7ad2 is prepared as appropriate phenol derivatives, (2- methylpyrazole -3- bases) methanol conduct
Appropriate alcohol, the intermediate formed according to universal method VII is then hydrolyzed, obtain embodiment 3.HRMS C40H41ClFN7O4S is counted
Calculation value：769.2613, measured value：385.6378(M+2H)
Embodiment 4：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -
6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- [(2- ethyoxyls pyrimidine-4-yl) methoxyl group]-D-phenylalanine
With
Embodiment 5：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -
6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- [(2- ethyoxyls pyrimidine-4-yl) methoxyl group]-D-phenylalanine
Using universal method VI, 7a is prepared as appropriate phenol derivatives, C1 is prepared as appropriate alcohol, then hydrolyzes
The intermediate formed according to universal method VII, obtain the mixture of diastereoisomer.They pass through preparative reverse-phase chromatography point
From using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile obtain embodiment 4 as eluent, be compared with
The diastereoisomer early eluted.HRMS C42H43ClFN7O5S calculated values：811.2719, measured value：406.6417(M+2H)
Obtain embodiment 5, the diastereoisomer eluted after being.HRMS C42H43ClFN7O5S calculated values：811.2719
Measured value：406.6436(M+2H)
Embodiment 6：2- [(1- butyl -1H- pyrazoles -5- bases) methoxyl group]-N- [(5Sa) -5- { 3- chloro -2- methyl -4-
[2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid
Using universal method VI, 7ad2 is prepared as appropriate phenol derivatives, prepares C2 as appropriate alcohol, Ran Houshui
The intermediate that solution is formed according to universal method VII, obtain embodiment 6.HRMS C43H47ClFN7O4S calculated values：811.3082, it is real
Measured value：406.6616(M+2H)
Embodiment 7：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -
6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-
Phenylalanine
Using universal method VI, 7ad2 is prepared as appropriate phenol derivatives, prepares C3 as appropriate alcohol, Ran Houshui
The intermediate that solution is formed according to universal method VII, obtain embodiment 7.HRMS C47H45ClFN7O5S calculated values：873.2875, it is real
Measured value：437.6498(M+2H)
Embodiment 8：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -
6- (furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine
With
Embodiment 9：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -
6- (furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine
Using universal method Ic, 4b is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- methoxyphenyls) propionic acid is non-right more early to elute as appropriate amino acid derivativges, acquisition embodiment 8
Reflect isomers.HRMS C34H36ClN5O5S calculated values：661.2126, measured value：662.2203(M+H)
Obtain embodiment 9, the diastereoisomer eluted after being.HRMS C34H36ClN5O5S calculated values：661.2126, it is real
Measured value：662.2203(M+H)
Embodiment 10：2- chloros-N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (furans -2- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine, diastereoisomer 1
Using universal method Ic, 4b is prepared as appropriate 4- chloros-thieno [2,3-d], (2R) -2- amino -3- (2-
Chlorophenyl) propionic acid as appropriate amino acid derivativges, obtains embodiment 10, for the diastereoisomer more early eluted.
HRMS C33H33Cl2N5O4S calculated values：665.1630, measured value：666.1670(M+H)
Embodiment 11：2- carbamoyls-N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethoxies
Base] phenyl } -6- (furans -2- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
Step A：5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] fluoro- 6- (2- of -4-
Furyl) thieno [2,3-d] pyrimidine
150mg is prepared into the mixture of 4b (0.3mMol) and 380mg silver fluorides (3.0mMol) in 6mL toluene in backflow
At a temperature of heat 3 hours.It is then cooled to room temperature, filtering inorganic component.Filtrate decompression is concentrated, obtains crude material,
It need not be further purified and be used directly for next step.
Step B：Embodiment 11
By 316mg 5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] fluoro- 6- of -4-
(2R) -2- amino -3- (2- Carbamoylphenyls) of (2- furyls) thieno [2,3-d] pyrimidine (0.65mMol), 271mg
The Cs of propionic acid (1.30mMol) and 424mg2CO3The mixture of (1.30mMol) in 6mL DMSO stirs 30 minutes in 40 DEG C.Will
Mixture is diluted with water, and is adjusted pH to 5 using 1M HCl solutions, is extracted with DCM.Organic phase is dried over sodium sulfate, filters, will
Filtrate decompression concentrates.Crude material is used as using the 0.1% TFA aqueous solution and acetonitrile and washed by preparative Reverse phase chromatography
De- liquid.The diastereoisomer more early eluted is collected, is embodiment 11.HRMS C34H35ClN6O5S calculated values：674.2078, it is real
Measured value：675.2146(M+H)
Embodiment 12：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- (pyridine -2- ylmethoxies)-D-phenylalanine
With
Embodiment 13：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- (pyridine -2- ylmethoxies)-D-phenylalanine
Using universal method Ic, 4b is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A5
As appropriate amino acid derivativges, embodiment 12, the diastereoisomer eluted after being are obtained.HRMS C39H39ClN6O5S is counted
Calculation value：738.2391, measured value：370.1269(M+2H)
Embodiment 13 is obtained, for the diastereoisomer more early eluted.HRMS C39H39ClN6O5S calculated values：
738.2391, measured value：370.1263(M+2H)
Embodiment 14：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- hydroxyls-D-phenylalanine
Step A：(2R)-2-[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base] the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid
Using universal method Ic, 4a is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, is obtained
(2R) -2- amino -3- (2- hydroxy phenyls) propionic acid, it is the mixture of diastereoisomer.They can pass through HILIC chromatograms point
From.Obtain (2R) -2- [[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6-
Iodo- thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid, the diastereoisomer eluted after being.MS
(M+H)：708.0
Step B：Embodiment 14
Using universal method IIIb, (2R) -2- [[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methyl piperazines -1-
Base) ethyoxyl] phenyl] the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] amino] conduct of -3- (2- hydroxy phenyls) propionic acid is suitably
The iodo- thienos of 6- [2,3-d] pyrimidine derivatives, 2- (the fluoro- 2- furyls of 5-) -4,4,5,5- tetramethyls -1,3,2- dioxas
Ring pentaborane obtains embodiment 14 as appropriate boric ester derivative.HRMS C33H33ClFN5O5S calculated values：665.1875
Measured value：333.6012(M+2H)
Embodiment 15：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine
With
Embodiment 16：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine
Using universal method Ib, 4c is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- methoxyphenyls) propionic acid obtains embodiment 15, the diastereomeric eluted after being as appropriate amino acid derivativges
Isomers.HRMS C34H35ClFN5O5S calculated values：679.2031, measured value：680.2100(M+H)
Embodiment 16 is obtained, for the diastereoisomer more early eluted.HRMS C34H35ClFN5O5S calculated values：
679.2031, measured value：680.2092(M+H)
Embodiment 17：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- (2,2,2- trifluoro ethoxies)-D-phenylalanine
Step A：(2R)-2-[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base] the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) ethyl propionate
By 876mg (2R) -2- [[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl]
Phenyl] the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid (1.24mMol) is dissolved in 5mL second
Alcohol, the 0.05mL concentrated sulfuric acids are then added, mixture is stirred 2 hours in 70 DEG C.Then mixture is diluted with water, using 1M
NaHCO3Solution adjusts pH to 5, is extracted with DCM.Organic phase is dried over sodium sulfate, filtering, filtrate decompression is concentrated.Crude product produces
Thing, using DCM and MeOH as eluent, obtains (2R) -2- [[(5S by purification by flash chromatographya) -5- [3- chloro -2- first
Base -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] amino] -3- (2-
Hydroxy phenyl) ethyl propionate.MS(M+H)：736.1
Step B：(2R)-2-[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base] the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] amino] -3- [2- (2,2,2- trifluoro ethoxies) phenyl] ethyl propionate
By 648mg (2R) -2- [[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethoxies
Base] phenyl] the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) ethyl propionates (0.88mMol) are molten
In 10mL DMF, 415mg K is then added at room temperature2CO3(3.00mMol) and 348mg 2,2,2- trifluoroethyl fluoroforms
Sulphonic acid ester (1.50mMol).Mixture is stirred 5 hours in 50 DEG C.Reactant mixture is diluted with salt solution, extracted with DCM.Have
Machine is mutually dried over sodium sulfate, filtering, filtrate decompression is concentrated.Crude material is made by purification by flash chromatography using DCM and methanol
For eluent, (2R) -2- [[(5S are obtaineda) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base] the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] amino] -3- [2- (2,2,2- trifluoro ethoxies) phenyl] ethyl propionate.MS
(M+H)：818.1
Step C：Embodiment 17
By (2R) -2- [[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -
The iodo- thienos of 6- [2,3-d] pyrimidine-4-yl] amino] -3- [2- (2,2,2- trifluoro ethoxies) phenyl] ethyl propionates are according to logical
Hydrolyzed with method VII, obtain (2R) -2- [[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethoxies
Base] phenyl] the iodo- thienos of -6- [2,3-d] pyrimidine-4-yl] amino] -3- [2- (2,2,2- trifluoro ethoxies) phenyl] propionic acid.
The compound may be used as the iodo- thienos of appropriate 6- [2,3-d] pyrimidine derivatives, and implementation is converted into according to universal method IIIb
Example 17, using 2- (the fluoro- 2- furyls of 5-) -4,4,5,5- tetramethyls -1,3,2- dioxaborolanes are as appropriate boric acid
Derivative.HRMS C35H34ClF4N5O5S calculated values：747.1905, measured value：374.6006(M+2H)
Embodiment 18：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- (pyridine -2- ylmethoxies)-D-phenylalanine
With
Embodiment 19：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- (pyridine -2- ylmethoxies)-D-phenylalanine
Using universal method Ic, 4c is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A5
As appropriate amino acid derivativges, embodiment 18 is obtained, for the diastereoisomer more early eluted.HRMS
C39H38ClFN6O5S calculated values：756.2296, measured value：379.1230(M+2H)
Obtain embodiment 19, the diastereoisomer eluted after being.HRMS C39H38ClFN6O5S calculated values：756.2296
Measured value：379.1230(M+2H)
Embodiment 20：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- [(1- methyl isophthalic acid H- pyrazoles -5- bases) methoxyl group] -
D-phenylalanine
Using universal method IIIb, 5b is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives, 2- (5-
Fluoro- 2- furyls) -4,4,5,5- tetramethyls -1,3,2- dioxaborolanes are implemented as appropriate boronic acid derivatives
Example 20.HRMS C38H39ClFN7O5S calculated values：759.2406, measured value：380.6271(M+2H)
Embodiment 21：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- [(1- ethyl -1H- pyrazoles -5- bases) methoxyl group] -
D-phenylalanine
Using universal method IIIb, 5c is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives, 2- (5-
Fluoro- 2- furyls) -4,4,5,5- tetramethyls -1,3,2- dioxaborolanes are implemented as appropriate boronic acid derivatives
Example 21.HRMS C39H41ClFN7O5S calculated values：773.2562, measured value：387.6358(M+2H)
Embodiment 22：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- [(2- ethyoxyls pyrimidine-4-yl) methoxyl group]-D-
Phenylalanine
Using universal method Ic, 4c is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A2
As appropriate amino acid derivativges, embodiment 22, the diastereoisomer eluted after being are obtained.HRMS C40H41ClFN7O6Meter
Calculation value S：801.2512, measured value：401.6326(M+2H)
Embodiment 23：2- [(1- butyl -1H- pyrazoles -5- bases) methoxyl group]-N- [(5Ra) -5- { 3- chloro -2- methyl -4-
[2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl]-D-
Phenylalanine
With
Embodiment 24：2- [(1- butyl -1H- pyrazoles -5- bases) methoxyl group]-N- [(5Sa) -5- { 3- chloro -2- methyl -4-
[2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl]-D-
Phenylalanine
Using universal method Ic, 4c is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A3
As appropriate amino acid derivativges, embodiment 23 is obtained, for the diastereoisomer more early eluted.HRMS
C41H45ClFN7O5S calculated values：801.2875, measured value：401.6502(M+2H)
Obtain embodiment 24, the diastereoisomer eluted after being.HRMS C41H45ClFN7O5S calculated values：801.2875
Measured value：401.6505(M+2H)
Embodiment 25：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2,2,2- trifluoro ethoxies) pyrimidine -4-
Base] methoxyl group }-D-phenylalanine
With
Embodiment 26：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2,2,2- trifluoro ethoxies) pyrimidine -4-
Base] methoxyl group }-D-phenylalanine
Using universal method Ic, 4c is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A8
As appropriate amino acid derivativges, embodiment 25 is obtained, for the diastereoisomer more early eluted.HRMS
C40H38ClF4N7O6S calculated values：855.2228, measured value：428.6181(M+2H)
Obtain embodiment 26, the diastereoisomer eluted after being.HRMS C40H38ClF4N7O6S calculated values：
855.2228, measured value：428.6193(M+2H)
Embodiment 27：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] first
Epoxide }-D-phenylalanine
Step A：(2R)-2-[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base] -6- (the fluoro- 2- furyls of 5-) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) ethyl propionate
0.97g embodiments 14 (1.46mMol) are dissolved in 15mL HCl solutions (1.25M EtOH solution), in 40 DEG C of stirrings
Overnight.Mixture is cooled to room temperature, using NaHCO3The aqueous solution is neutralized, and mixture is extracted with DCM.Organic phase is done through sodium sulphate
It is dry, filtering, filtrate decompression is concentrated.Residue, using DCM and MeOH as eluent, is obtained by purification by flash chromatography
(2R)-2-[[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6- (fluoro- 2- of 5-
Furyl) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) ethyl propionate.
1H NMR(400MHz,DMSO-d6)δ：9.48(br s,1H),8.39(s,1H),7.30(s,2H),7.01(td,
1H),6.72(d,1H),6.64(t,1H),6.41(d,1H),5.83(m,1H),5.56(t,1H),5.08(d,1H),4.94(m,
1H),4.30(t,2H),4.03(m,2H),3.07(dd,1H),2.81(t,2H),2.56(br,4H),2.36(dd,1H),2.32
(br,4H),2.14(s,3H),1.91(s,3H)
MS(M+H)：694.2
Step B：Embodiment 27
Using universal method VI, (2R) -2- [[(5Sa) -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls)
Ethyoxyl] phenyl] -6- (the fluoro- 2- furyls of 5-) thieno [2,3-d] pyrimidine-4-yl] amino] -3- (2- hydroxy phenyls) propionic acid
Ethyl ester prepares C3 as appropriate 01 derivatives, then hydrolyzes and formed according to universal method VII as appropriate phenol derivatives
Intermediate, obtain embodiment 27.HRMSC45H43ClFN7O6S calculated values：863.2668, measured value：432.6414(M+2H)
Embodiment 28：N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6-
(5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl] -2- hydroxyls-D-phenylalanine
Step A：2- [2- chloros -4- [4- chloros -6- (the fluoro- 2- furyls of 5-) thieno [2,3-d] pyrimidine -5- bases] -3-
Methyl-phenoxv]-N, N- dimethyl-ethylamines
Using universal method IIIb, 4e is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine derivatives, 2- (5-
Fluoro- 2- furyls) -4,4,5,5- tetramethyls -1,3,2- dioxaborolanes obtain 2- as appropriate boronic acid derivatives
[2- chloros -4- [4- chloros -6- (the fluoro- 2- furyls of 5-) thieno [2,3-d] pyrimidine -5- bases] -3- methyl-phenoxvs]-N,
N- dimethyl-ethylamines.
Step B：Embodiment 28
Using universal method Ib, [[4- chloros -6- (the fluoro- 2- furyls of 5-) thieno [2,3-d] is phonetic by 2- chloros -4- by 2-
Pyridine -5- bases] -3- methyl-phenoxvs]-N, N- dimethyl-ethylamines are as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivates
Thing, 2- hydroxyls-D-phenylalanine obtain embodiment 28, the diastereo-isomerism eluted after being as appropriate amino acid derivativges
Body.HRMS C30H28ClFN4O5S calculated values：610.1453, measured value：611.1503(M+H)
Embodiment 29：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (thiene-3-yl) thieno [2,3-d] pyrimidine-4-yl] -3- pyridines -2- bases-D-alanine
With
Embodiment 30：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (thiene-3-yl) thieno [2,3-d] pyrimidine-4-yl] -3- pyridines -2- bases-D-alanine
Using universal method Ic, 4g is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- pyridine radicals) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through
Preparative reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.
Embodiment 29 is obtained, for the diastereoisomer more early eluted.HRMS C32H33ClN6O3S2Calculated value：648.1744, actual measurement
Value：649.1811(M+H)
Obtain embodiment 30, the diastereoisomer eluted after being.HRMS C32H33ClN6O3S2Calculated value：648.1744
Measured value：649.1816(M+H)
Embodiment 31：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (thiene-3-yl) thieno [2,3-d] pyrimidine-4-yl] -3- cyclohexyl-D-alanine
With
Embodiment 32：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (thiene-3-yl) thieno [2,3-d] pyrimidine-4-yl] -3- cyclohexyl-D-alanine
Using universal method Ic, 4g is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- cyclohexyl-propionic acid obtains embodiment 31, for the diastereo-isomerism more early eluted as appropriate amino acid derivativges
Body.HRMS C33H40ClN5O3S2Calculated value：653.2261, measured value：327.6194(M+2H)
Obtain embodiment 32, the diastereoisomer eluted after being.HRMS C33H40ClN5O3S2Calculated value：653.2261
Measured value：327.6195(M+2H)
Embodiment 33：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (thiene-3-yl) thieno [2,3-d] pyrimidine-4-yl] the fluoro- D-phenylalanines of -2-
With
Embodiment 34：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (thiene-3-yl) thieno [2,3-d] pyrimidine-4-yl] the fluoro- D-phenylalanines of -2-
Using universal method Ic, 4g is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- fluorophenyls) propionic acid obtains embodiment 33, the diastereo-isomerism eluted after being as appropriate amino acid derivativges
Body.HRMS C33H33ClFN5O3S2Calculated value：665.1697, measured value：666.1776(M+H)
Embodiment 34 is obtained, for the diastereoisomer more early eluted.HRMS C33H33ClFN5O3S2Calculated value：
665.1697, measured value：666.1776(M+H)
Embodiment 35：N-[(5Ra) -5- { 3- chloro -2- methyl -4- [2- (morpholine -4- bases) ethyoxyl] phenyl } -6- (thiophenes
Fen -3- bases) thieno [2,3-d] pyrimidine-4-yl] -3- pyridines -2- bases-D-alanine
With
Embodiment 36：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (morpholine -4- bases) ethyoxyl] phenyl } -6- (thiophenes
Fen -3- bases) thieno [2,3-d] pyrimidine-4-yl] -3- pyridines -2- bases-D-alanine
Using universal method Ic, 4h is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- pyridine radicals) propionic acid obtains embodiment 35, is different compared with the diastereomeric early eluted as appropriate amino acid derivativges
Structure body.HRMS C31H30ClN5O4S2Calculated value：635.1428, measured value：636.1499(M+H)
Obtain embodiment 36, the diastereoisomer eluted after being.HRMS C31H30ClN5O4S2Calculated value：635.1428
Measured value：636.1508(M+H)
Embodiment 37：2- (amino methyl)-N- [(5Ra) -5- { 3- chloro -2- methyl -4- [2- (morpholine -4- bases) ethoxies
Base] phenyl } -6- (thiene-3-yl) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
With
Embodiment 38：2- (amino methyl)-N- [(5Sa) -5- { 3- chloro -2- methyl -4- [2- (morpholine -4- bases) ethoxies
Base] phenyl } -6- (thiene-3-yl) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
Using universal method Ic, 4h is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- [2- (amino methyl) phenyl] propionic acid obtains embodiment 37, more early eluted as appropriate amino acid derivativges
Diastereoisomer.HRMS C33H34ClN5O4S2Calculated value：663.1741, measured value：664.1808(M+H)
Obtain embodiment 38, the diastereoisomer eluted after being.HRMS C33H34ClN5O4S2Calculated value：663.1741
Measured value：664.1825(M+H)
Embodiment 39：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine
Using universal method VI, 7b is prepared as appropriate phenol derivatives, and methanol is as appropriate 01 derivatives, then
The intermediate that hydrolysis is formed according to universal method VII, obtain embodiment 39.HRMS C33H36ClN5O4S calculated values：633.2176
Measured value：317.6163(M+2H)
Embodiment 40：2- [(1- tert-butyl -1H- pyrazoles -5- bases) methoxyl group]-N- [(5Sa) -5- { 3- chloro -2- first
Base -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
Using universal method VI, 7b is prepared as appropriate phenol derivatives, prepares C4 as appropriate 01 derivatives, so
The intermediate formed according to universal method VII is hydrolyzed afterwards, obtains embodiment 40.HRMS C40H46ClN7O4S calculated values：
755.3021 measured value：378.6573(M+2H)
Embodiment 41：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxy ethyls) pyrimidine-4-yl] first
Epoxide }-D-phenylalanine
Using universal method VI, 7b is prepared as appropriate phenol derivatives, prepares C5 as appropriate 01 derivatives, so
The intermediate formed according to universal method VII is hydrolyzed afterwards, obtains embodiment 41.HRMS C40H44ClN7O5S calculated values：
769.2813, measured value：385.6476(M+2H).
Embodiment 42：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [1- (2,2,2- trifluoroethyls) -1H- pyrazoles -5-
Base] methoxyl group }-D-phenylalanine
Using universal method VI, 7b is prepared as appropriate phenol derivatives, prepares C6 as appropriate 01 derivatives, so
The intermediate formed according to universal method VII is hydrolyzed afterwards, obtains embodiment 42.HRMS C38H39ClF3N7O4S calculated values：
781.2425, measured value：391.6300(M+2H)
Embodiment 43：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (morpholine -4- bases) pyrimidine-4-yl] methoxies
Base }-D-phenylalanine
Using universal method VI, 7b is prepared as appropriate phenol derivatives, prepares C7 as appropriate 01 derivatives, so
The intermediate formed according to universal method VII is hydrolyzed afterwards, obtains embodiment 43.HRMSC41H45ClN8O5S calculated values：
796.2922, measured value：399.1546(M+2H)
Embodiment 44：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2,2,2- trifluoro ethoxies) pyrimidine -4-
Base] methoxyl group }-D-phenylalanine
Using universal method VI, 7b is prepared as appropriate phenol derivatives, prepares C8 as appropriate 01 derivatives, so
The intermediate formed according to universal method VII is hydrolyzed afterwards, obtains embodiment 44.HRMSC39H39ClF3N7O5S calculated values：
809.2374, measured value：405.6262(M+2H)
Embodiment 45：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] first
Epoxide }-D-phenylalanine
Using universal method VI and 7b is prepared as appropriate phenol derivatives, prepares C3 as appropriate 01 derivatives,
Then the intermediate formed according to universal method VII is hydrolyzed, obtains embodiment 45.HRMSC44H44ClN7O5S calculated values：
817.2813, measured value：409.6494(M+2H)
Embodiment 46：N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6-
(propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [1- (2,2,2- trifluoroethyls) -1H- pyrazoles -5- bases] first
Epoxide }-D-phenylalanine
Using universal method VI, 7c is prepared as appropriate phenol derivatives, prepares C6 as appropriate 01 derivatives, so
The intermediate formed according to universal method VII is hydrolyzed afterwards, obtains embodiment 46.HRMS C35H34ClF3N6O4S calculated values：
726.2003, measured value：727.2092(M+H)
Embodiment 47：N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6-
(propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (morpholine -4- bases) pyrimidine-4-yl] methoxyl group }-D- benzene
Alanine
Using universal method VI, 7c is prepared as appropriate phenol derivatives, prepares C7 as appropriate 01 derivatives, so
The intermediate formed according to universal method VII is hydrolyzed afterwards, obtains embodiment 47.HRMSC38H40ClN7O5S calculated values：
741.2500, measured value：371.6331(M+2H)
Embodiment 48：N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6-
(propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2,2,2- trifluoro ethoxies) pyrimidine-4-yl] methoxies
Base }-D-phenylalanine
Using universal method VI, 7c is prepared as appropriate phenol derivatives, prepares C8 as appropriate 01 derivatives, so
The intermediate formed according to universal method VII is hydrolyzed afterwards, obtains embodiment 48.HRMSC36H34ClF3N6O5S calculated values：
754.1952, measured value：755.1971(M+H)
Embodiment 49：N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6-
(propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group } -
D-phenylalanine
Using universal method VI, 7c is prepared as appropriate phenol derivatives, prepares C3 as appropriate 01 derivatives, so
The intermediate formed according to universal method VII is hydrolyzed afterwards, obtains embodiment 49.HRMSC41H39ClN6O5S calculated values：
762.2391, measured value：371.6323(M+2H)
Embodiment 50：N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6-
(4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- fluorophenyls) pyrimidine-4-yl] methoxyl group }-D- phenylpropyl alcohol ammonia
Acid
Step A：(2R) -2- [[the bromo- 6- of 5- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2-
[[2- (2- fluorophenyls) pyrimidine-4-yl] methoxyl group] phenyl] ethyl propionate
Using universal method VI, 7d is prepared as appropriate phenol derivatives, prepares C9 as appropriate 01 derivatives,
[[[2- (2- fluorophenyls) is phonetic by 2- by -3- by (2R) -2- [[the bromo- 6- of 5- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino]
Pyridine -4- bases] methoxyl group] phenyl] ethyl propionate.1H NMR(400MHz,DMSO-d6)δ：8.84(d,1H),8.39(s,1H),
7.95(td,1H),7.58-7.52(m,3H),7.39-7.24(m,8H),7.13(d,1H),6.95(t,1H),5.29-5.15
(m,3H),4.16(q,2H),3.63(dd,1H),3.25(dd,1H),1.19(t,3H)
Step B：(2R) -2- [[5- [3- chloros -4- (2- dimethyl aminoethyls epoxide) -2- methylphenyls] -6- (4-
Fluorophenyl) thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2- [[2- (2- fluorophenyls) pyrimidine-4-yl] methoxyl group] phenyl]
Ethyl propionate
By 1eq. (2R) -2- [[the bromo- 6- of 5- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2-
[[2- (2- fluorophenyls) pyrimidine-4-yl] methoxyl group] phenyl] ethyl propionate and 1.2eq. prepare B5 and be dissolved in dioxane (5mL/
Mmol), 5mol%AtaPhos, 3eq.Cs are then added2CO3With water (5mL/mmol), by mixture in 70 DEG C of ar gas environments
Stirring is until being not observed further conversion.Then mixture is diluted with EtOAc, with salt water washing organic phases through sulphur
Sour sodium is dried, and filtering, filtrate decompression is concentrated.Crude material is by purification by flash chromatography, using DCM and MeOH as elution
Liquid, obtain (2R) -2- [[5- [3- chloros -4- (2- dimethyl aminoethyls epoxide) -2- methylphenyls] -6- (4- fluorophenyls)
Thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2- [[2- (2- fluorophenyls) pyrimidine-4-yl] methoxyl group] phenyl] propionic acid second
Ester, it is the mixture of diastereoisomer.MS(M+H)：834.6
Step C：Embodiment 50
Using universal method VII, (2R) -2- [[5- [3- chloros -4- (2- dimethyl aminoethyls epoxide) -2- methyl-benzene
Base] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2- [[2- (2- fluorophenyls) pyrimidine-4-yl] first
Epoxide] phenyl] ethyl propionate as appropriate ester derivant, obtains embodiment 50, the diastereoisomer eluted after being.HRMS
C43H37ClF2N6O4S calculated values：806.2254, measured value：807.2343(M+H)
Embodiment 51：N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6-
(4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- ({ 2- [2- (2- methoxy ethoxies) phenyl] pyrimidine-4-yl } first
Epoxide)-D-phenylalanine
Step A：(2R) -2- [[the bromo- 6- of 5- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2-
[[2- [2- (2- methoxy ethoxies) phenyl] pyrimidine-4-yl] methoxyl group] phenyl] ethyl propionate
Using universal method VI, 7d is prepared as appropriate phenol derivatives, prepares C10 as appropriate 01 derivatives,
(2R) -2- [[the bromo- 6- of 5- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2- [[2- [2- (2- methoxyl groups
Ethyoxyl) phenyl] pyrimidine-4-yl] methoxyl group] phenyl] ethyl propionate.1H NMR(400MHz,DMSO-d6)δ：8.80(d,1H),
8.41(s,1H),7.57-7.53(m,3H),7.46-7.23(m,7H),7.16(d,1H),7.07(d,1H),7.03(t,1H),
6.94(t,1H),5.28-5.23(m,1H),5.19(dd,2H),4.18-4.11(m,4H),3.61-3.57(m,3H),3.27
(dd,1H),3.21(s,3H),1.19(t,3H)
Step B：(2R) -2- [[5- [3- chloros -4- (2- dimethyl aminoethyls epoxide) -2- methylphenyls] -6- (4-
Fluorophenyl) thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2- [[2- [2- (2- methoxy ethoxies) phenyl] pyrimidine -4-
Base] methoxyl group] phenyl] ethyl propionate
By 1eq. (2R) -2- [[the bromo- 6- of 5- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2-
[[2- [2- (2- methoxy ethoxies) phenyl] pyrimidine-4-yl] methoxyl group] phenyl] ethyl propionate and 1.2eq. prepare B5 and be dissolved in
Dioxane (5mL/mmol), then add 5mol%AtaPhos, 3eq.Cs2CO3With water (5mL/mmol), by mixture in 70 DEG C
Stirring is until being not observed further conversion in ar gas environment.Then mixture is diluted with EtOAc, with salt water washing.
Organic phase is dried over sodium sulfate, filtering, filtrate decompression is concentrated.Crude material is by purification by flash chromatography, using DCM and MeOH
As eluent, (2R) -2- [[5- [3- chloros -4- (2- dimethyl aminoethyls epoxide) -2- methylphenyls] -6- (4- are obtained
Fluorophenyl) thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2- [[2- [2- (2- methoxy ethoxies) phenyl] pyrimidine -4-
Base] methoxyl group] phenyl] ethyl propionate, for the mixture of diastereoisomer.MS(M+H)：890.6
Step C：Embodiment 51
Using universal method VII, (2R) -2- [[5- [3- chloros -4- (2- dimethyl aminoethyls epoxide) -2- methyl-benzene
Base] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] amino] -3- [2- [[2- [2- (2- methoxy ethoxies) benzene
Base] pyrimidine-4-yl] methoxyl group] phenyl] ethyl propionate as appropriate ester derivant, obtains
Embodiment 51, the diastereoisomer eluted after being.HRMS C46H44ClFN6O6S calculated values：862.2716, actual measurement
Value：432.1442(M+2H)
Embodiment 52：N-[(5Ra) -5- (3,5- dichloro- -4- hydroxy-2-methyls phenyl) -6- ethylthiophenes simultaneously [2,3-
D] pyrimidine-4-yl]-D-phenylalanine
With
Embodiment 53：N-[(5Sa) -5- (3,5- dichloro- -4- hydroxy-2-methyls phenyl) -6- ethylthiophenes simultaneously [2,3-
D] pyrimidine-4-yl]-D-phenylalanine
Using universal method VII, 7f is prepared as appropriate ester derivant, obtains the mixture of diastereoisomer.It
By preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Obtain embodiment 52, be compared with
The diastereoisomer early eluted.HRMS C24H21Cl2N3O3S calculated values：501.0681, measured value：502.0755(M+H)
Obtain embodiment 53, the diastereoisomer eluted after being.HRMS C24H21Cl2N3O3S calculated values：501.0681
Measured value：502.0772(M+H)
Embodiment 54：N-((5Sa) -5- { 3,5- dichloro- -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl]
Phenyl } -6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
With
Embodiment 55：N-((5Ra) -5- { 3,5- dichloro- -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl]
Phenyl } -6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VI, 7f is prepared as appropriate phenol derivatives, 2- (4- methylpiperazine-1-yls) ethanol conduct
Appropriate 01 derivatives, the intermediate formed according to universal method VII is then hydrolyzed, obtain embodiment 54, what is eluted after being is non-
Enantiomter.HRMS C31H35Cl2N5O3S calculated values：627.1838, measured value：628.1935(M+H)
Embodiment 55 is obtained, for the diastereoisomer more early eluted.HRMS C31H35Cl2N5O3S calculated values：
627.1838, measured value：628.1932(M+H)
Embodiment 56：N-{(5Sa) -6- ethylthiophenes are simultaneously by -5- [3- chloros -4- (2- hydroxyl-oxethyls) -2- aminomethyl phenyls]
[2,3-d] pyrimidine-4-yl }-D-phenylalanine
Using universal method VI, prepare 7gd1 and spread out as appropriate phenol derivatives, 10eq. ethylene glycol as appropriate alcohol
Biology, the intermediate formed according to universal method VII is then hydrolyzed, obtain embodiment 56.HRMS C26H26ClN3O4S calculated values：
511.1333, measured value：512.1390(M+H)
Embodiment 57：N-{(5Sa) -6- ethylthiophenes are simultaneously by -5- [4- (Carboxvmethoxv) -3- chloro -2- aminomethyl phenyls]
[2,3-d] pyrimidine-4-yl }-D-phenylalanine
Using universal method VI, prepare 7gd1 and make as appropriate phenol derivatives, 2- hydroxy-ns, N- dimethyl acetamides
For appropriate 01 derivatives, the intermediate formed according to universal method VII is then hydrolyzed, obtains embodiment 57.HRMS
C26H24ClN3O5S calculated values：525.1125, measured value：526.1217(M+H)
Embodiment 58：N-((5Ra) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- second
Base thieno [2,3-d] pyrimidine-4-yl)-L-phenylalanine
With
Embodiment 59：N-((5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- second
Base thieno [2,3-d] pyrimidine-4-yl)-L-phenylalanine
Using universal method VI, 7g is prepared as appropriate phenol derivatives, 2- (dimethylamino) ethanol is as appropriate
01 derivatives, then hydrolyze the intermediate formed according to universal method VII, obtain the mixture of diastereoisomer.They
By preparative reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile, which are used as, to be washed
De- liquid.Embodiment 58 is obtained, for the diastereoisomer more early eluted.HRMS C28H31ClN4O3S calculated values：538.1805, it is real
Measured value：539.1869(M+H)
Obtain embodiment 59, the diastereoisomer eluted after being.HRMS C28H31ClN4O3S calculated values：538.1805
Measured value：539.1866(M+H)
Embodiment 60：N-((5Sa) -5- { 3- chloros -4- [3- (dimethylamino) propoxyl group] -2- aminomethyl phenyls } -6- second
Base thieno [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VI, 7gd1 is prepared as appropriate phenol derivatives, 3- (dimethylamino) propyl alcohol is as suitable
When 01 derivatives, then hydrolyze according to universal method VII formed intermediate, obtain embodiment 60.HRMS
C29H33ClN4O3S calculated values：552.1962, measured value：553.2036(M+H)
Embodiment 61：N-((5Sa) -5- { 3- chloro -2- methyl -4- [2- (morpholine -4- bases) ethyoxyl] phenyl } -6- second
Base thieno [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VI, 7gd1 is prepared as appropriate phenol derivatives, 2- morpholinoes ethanol is as appropriate alcohol
Derivative, the intermediate formed according to universal method VII is then hydrolyzed, obtain embodiment 61.HRMS C30H33ClN4O4S is calculated
Value：580.1911, measured value：581.1981(M+H)
Embodiment 62：N-((5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
With
Embodiment 63N- ((5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -
6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VI, 7g is prepared as appropriate phenol derivatives, 2- (4- methylpiperazine-1-yls) ethanol conduct
Appropriate 01 derivatives, the intermediate formed according to universal method VII is then hydrolyzed, obtain embodiment 62, more early elute
Diastereoisomer.HRMS C31H36ClN5O3S calculated values：593.2227, measured value：594.2313(M+H)
Obtain embodiment 63, the diastereoisomer eluted after being.HRMS C31H36ClN5O3S calculated values：593.2227
Measured value：594.2304(M+H)
Embodiment 64：N-((5Sa) -5- { 3- chloro -2- methyl -4- [3- (4- methylpiperazine-1-yls) propoxyl group] benzene
Base } -6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VI, 7gd1 is prepared as appropriate phenol derivatives, 3- (4- methylpiperazine-1-yls) propyl- 1-
Then alcohol hydrolyzes the intermediate formed according to universal method VII, obtains embodiment 64 as appropriate 01 derivatives.HRMS
C32H38ClN5O3S calculated values：607.2384, measured value：608.2444(M+H)
Embodiment 65：N-((5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- [5- (methoxycarbonyl) -4- methylfuran -2- bases] thieno [2,3-d] pyrimidine-4-yl) -2- methoxyl group-D- phenylpropyl alcohols
Propylhomoserin
With
Embodiment 66：N-((5Ra) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- [5- (methoxycarbonyl) -4- methylfuran -2- bases] thieno [2,3-d] pyrimidine-4-yl) -2- methoxyl group-D- phenylpropyl alcohols
Propylhomoserin
Step A：[4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] thiophene
And [2,3-d] pyrimidine -6- bases]-trimethyl-stannane
In ar gas environment, by 1.97g 4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls)
Ethyoxyl] phenyl] thieno [2,3-d] pyrimidine (4.50mMol, obtained from the step A for preparing 4a) is dissolved in the anhydrous THF of 40mL, and will be mixed
Compound is cooled to -78 DEG C.Then add 4.5mL LDA (9mMol, 2M heptane, THF and ethyl benzole soln), by mixture in-
78 DEG C are stirred 1 hour.Then 13.5mL Me are added3SnCl solution (13.5mMol, 1M hexane solution), mixture is warmed
To room temperature.Then by mixture cc.NH4Cl solution dilutes, and is extracted with ether.Organic phase is dried over sodium sulfate, filtering, will filter
Liquid is concentrated under reduced pressure.60mL EtOAc are then dissolved in, the NaF solution of 40mL saturations is added, it is stirred overnight at room temperature.
Then filtered, separating filtrate phase.Aqueous phase is extracted with EtOAc.The organic phase of merging is dried over sodium sulfate, filtering, by filtrate
It is concentrated under reduced pressure.Crude material, using DCM and MeOH as eluent, obtains [4- chloros -5- [3- chlorine by purification by flash chromatography
Generation -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] thieno [2,3-d] pyrimidine -6- bases]-trimethyl-tin
Alkane.HRMS C23H30N4OSCl2Sn calculated values：600.0539, measured value：601.0584(M+H)
Step B：5- [4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] thiophenes
Fen simultaneously [2,3-d] pyrimidine -6- bases] -3- methyl-ribofuranosyl -2- methyl formates
By 900mg [4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl]
Thieno [2,3-d] pyrimidine -6- bases]-trimethyl-stannane (1.50mMol), the bromo- 3- methyl-ribofuranosyls -2- formic acid of 657mg 5-
Methyl esters (3mMol), 29mg CuI (0.15mMol), 29mg Pd (PhCN)2Cl2(0.075mMol)、46mg Ph3As
(0.15mMol) and 2mL NMP are in 100 DEG C of stirrings until further conversion is not observed.Then by mixture EtOAc
Dilution, is washed with the NaF solution of saturation.Aqueous phase is extracted with EtOAc.The organic phase of merging is dried over sodium sulfate, filtering, by filtrate
It is concentrated under reduced pressure.Crude material, using DCM and MeOH as eluent, obtains 5- [4- chloro -5- [3- by purification by flash chromatography
Chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] thieno [2,3-d] pyrimidine -6- bases] -3- methyl -
Furans -2- methyl formates.HRMS C27H28Cl2N4O4S calculated values：574.1208, measured value：575.1263(M+H)
Step C：Embodiment 65
Using universal method Ib, 5- [4- chloros -5- [3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethoxies
Base] phenyl] thieno [2,3-d] pyrimidine -6- bases] -3- methyl-ribofuranosyl -2- methyl formates are as appropriate 4- chloros-thieno
[2,3-d] pyrimidine derivatives, (2R) -2- amino -3- (2- methoxyphenyls) propionic acid obtain as appropriate amino acid derivativges
Embodiment 65, for the diastereoisomer more early eluted.HRMS C37H40ClN5O7S calculated values：733.23369, measured value：
367.6263(M+2H)
Obtain embodiment 66, the diastereoisomer eluted after being.HRMS C37H40ClN5O7S calculated values：733.23369
Measured value：367.6223(M+2H)
Embodiment 67：N- [6- ethyls -5- (3- hydroxy-2-methyls phenyl) thieno [2,3-d] pyrimidine-4-yl]-D- benzene
Alanine
Using universal method IId, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 2- methyl-
3- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- bases) phenol as appropriate boronic acid derivatives, is implemented
Example 67, it is the mixture of diastereoisomer.HRMS C24H23N3O3S calculated values：433.1460, measured value：434.1545 and
434.1535(M+H)
Embodiment 68：N- [6- ethyls -5- (3- fluoro-2-methylbenzenes base) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohols
Propylhomoserin
Using universal method IIa, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, (the fluoro- 2- of 3-
Methylphenyl) boric acid as appropriate boronic acid derivatives, obtains embodiment 68, and it is the mixture of diastereoisomer.HRMS
C24H22FN3O2S calculated values：435.1417, measured value：436.1489 with 436.1484 (M+H)
Embodiment 69：N- [6- ethyls-(5Sa) -5- (3- fluoro-2-methylbenzenes base) thieno [2,3-d] pyrimidine-4-yl] -
D-phenylalanine
With
Embodiment 70：N- [6- ethyls-(5Ra) -5- (3- fluoro-2-methylbenzenes base) thieno [2,3-d] pyrimidine-4-yl] -
D-phenylalanine
The diastereoisomer of embodiment 68 is by preparative reversed phase chromatography separation, using 25mM NH4HCO3The aqueous solution and
Acetonitrile is as eluent.Embodiment 69 is obtained, for the diastereoisomer more early eluted.HRMS C24H22FN3O2S calculated values：
435.1417, measured value：436.1481(M+H)
Obtain embodiment 70, the diastereoisomer eluted after being.HRMS C24H22FN3O2S calculated values：435.1417, it is real
Measured value：436.1498(M+H)
Embodiment 71：N- [6- ethyls -5- (1H- indoles -7- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid, diastereoisomer 1
With
Embodiment 72：N- [6- ethyls -5- (1H- indoles -7- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid, diastereoisomer 2
Using universal method IIa, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 7- (4,4,
5,5- tetramethyls -1,3,2- dioxaborolanes -2- bases) -1H- indoles as appropriate boronic acid derivatives, obtains diastereomeric
The mixture of isomers.They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.
Embodiment 71 is obtained, for the diastereoisomer more early eluted.HRMS C25H22N4O2S calculated values：442.1463, measured value：
443.1540(M+H)
Obtain embodiment 72, the diastereoisomer eluted after being.HRMS C25H22N4O2S calculated values：442.1463, it is real
Measured value：443.1537(M+H)
Embodiment 73：N- [6- ethyls-(5Sa) -5- (1H- indoles -4- bases) thieno [2,3-d] pyrimidine-4-yl]-D- benzene
Alanine
With
Embodiment 74：N- [6- ethyls-(5Ra) -5- (1H- indoles -4- bases) thieno [2,3-d] pyrimidine-4-yl]-D- benzene
Alanine
7h diastereoisomer is prepared by preparative reversed phase chromatography separation, is made using the 0.1%TFA aqueous solution and acetonitrile
For eluent.Embodiment 73 is obtained, for the diastereoisomer more early eluted.HRMS C25H22N4O2S calculated values：442.1463
Measured value：443.1529(M+H)
Obtain embodiment 74, the diastereoisomer eluted after being.HRMS C25H22N4O2S calculated values：442.1463, it is real
Measured value：443.1538(M+H)
Embodiment 75：N- [6- ethyls-(5Sa) -5- (3- methoxyl group -2- aminomethyl phenyls) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
With
Embodiment 76：N- [6- ethyls-(5Ra) -5- (3- methoxyl group -2- aminomethyl phenyls) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
Using universal method IIb, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 2- (3- first
Epoxide -2- methylphenyls) -4,4,5,5- tetramethyls -1,3,2- dioxaborolanes are adopted as appropriate boronic acid derivatives
Use DME:Water 5:1 replaces 2-Me-THF, by preparative reversed phase chromatography separation diastereoisomer, using 25mM NH4HCO3Water
Solution and acetonitrile obtain embodiment 75, for the diastereoisomer more early eluted as eluent.HRMS C25H25N3O3S is calculated
Value：447.1617, measured value：448.1701(M+H)
Obtain embodiment 76, the diastereoisomer eluted after being.HRMS C25H25N3O3S calculated values：447.1617, it is real
Measured value：448.1672(M+H)
Embodiment 77：N-[(5Ra) -5- (2- chloro -3- picoline -4- bases) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -
4- yls]-D-phenylalanine
With
Embodiment 78N- [(5Sa) -5- (2- chloro -3- picoline -4- bases) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -
4- yls]-D-phenylalanine
Using universal method IIb, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 2- chloros-
3- methyl -4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- bases) pyridines as appropriate boronic acid derivatives,
Using DME:Water 5:1 replaces 2-Me-THF, water-soluble using 0.1%TFA by preparative reversed phase chromatography separation diastereoisomer
Liquid and acetonitrile obtain embodiment 77, for the diastereoisomer more early eluted as eluent.HRMS C23H21ClN4O2S is calculated
Value：452.1074, measured value：453.1158(M+H)
Obtain embodiment 78, the diastereoisomer eluted after being.HRMS C23H21ClN4O2S calculated values：452.1074
Measured value：453.1165(M+H)
Embodiment 79：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
Using universal method IIb, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 4,4,5,5-
Tetramethyl -2- (1- naphthyls) -1,3,2- dioxaborolanes obtain diastereoisomer as appropriate boronic acid derivatives
Mixture.By it by preparative Reverse phase chromatography, using the 0.1%TFA aqueous solution and acetonitrile as eluent, implemented
Example 79, it is non-enantiomer mixture.HRMS C27H23N3O2S calculated values：453.1511, measured value：454.1580 and
454.1580(M+H)
Embodiment 80：N- [6- ethyls -5- (quinoline -5- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
Using universal method IIa, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 5- (4,4,
5,5- tetramethyls -1,3,2- dioxaborolanes -2- bases) as appropriate boronic acid derivatives, it is different to obtain diastereomeric quinolone
The mixture of structure body.By it by preparative Reverse phase chromatography, using 40mM NH4The OAc aqueous solution (pH=4, using AcOH
Regulation) and acetonitrile as eluent.Embodiment 80 is obtained, is the mixture of diastereoisomer.HRMS C26H22N4O2S is calculated
Value：454.1463, measured value：455.1554 with 455.1518 (M+H)
Embodiment 81：N- [6- ethyls-(5Sa) -5- (isoquinolin -4- bases) thieno [2,3-d] pyrimidine-4-yl]-D- benzene
Alanine
With
Embodiment 82：N- [6- ethyls-(5Ra) -5- (isoquinolin -4- bases) thieno [2,3-d] pyrimidine-4-yl]-D- benzene
Alanine
Step A：4- chloro -6- ethyls -5- (4- isoquinolyls) thieno [2,3-d] pyrimidine
Using universal method IIc, 2a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine, 4- (4,4,5,5- tetra-
Methyl isophthalic acid, 3,2- dioxaborolanes -2- bases) isoquinolin as appropriate boronic acid derivatives, obtain 4- chloro -6- ethyls -
5- (4- isoquinolyls) thieno [2,3-d] pyrimidine.
1H NMR(500MHz,DMSO-d6)δ：9.46(s,1H),8.93(s,1H),8.50(s,1H),8.26(m,1H),
7.74(m,2H),7.42(m,1H),2.65(q,2H),1.14(t,3H)
HRMS C17H12ClN3S calculated values：325.0440；Measured value：326.0502(M+H)
Step B：N- [6- ethyls -5- (isoquinolin -4- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
Using universal method Ia, step A product is as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D-
Phenylalanine is as appropriate amino acid derivativges, and obtaining N-, [6- ethyls -5- (isoquinolin -4- bases) thieno [2,3-d] is phonetic
Pyridine -4- bases]-D-phenylalanine, for the mixture of diastereoisomer.They are by preparative reversed phase chromatography separation, using water
With acetonitrile as eluent.Embodiment 81 is obtained, for the diastereoisomer more early eluted.HRMS C26H22N4O2S calculated values：
454.1463, measured value：455.1526(M+H)
Obtain embodiment 82, the diastereoisomer eluted after being.HRMS C26H22N4O2S calculated values：454.1463, it is real
Measured value：455.1538(M+H)
Embodiment 83：N- [6- ethyls-(5Sa) -5- (1- Methyl-1H-indole -7- bases) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
With
Embodiment 84：N- [6- ethyls-(5Ra) -5- (1- Methyl-1H-indole -7- bases) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
Using universal method IIb, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 1- methyl-
For 7- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- bases) indoles as appropriate boronic acid derivatives, it is non-right to obtain
Reflect the mixture of isomers.They are by preparative reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution (pH=4, uses
AcOH adjust) and acetonitrile as eluent.Embodiment 83 is obtained, for the diastereoisomer more early eluted.HRMS
C26H24N4O2S calculated values：456.1620, measured value：457.1671(M+H)
Obtain embodiment 84, the diastereoisomer eluted after being.HRMS C26H22N4O2S calculated values：456.1620, it is real
Measured value：457.1701(M+H)
Embodiment 85：N- [6- ethyls-(5Sa) -5- (3- Methyl-1H-indole -4- bases) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
With
Embodiment 86：N- [6- ethyls-(5Ra) -5- (3- Methyl-1H-indole -4- bases) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
Using universal method IIc, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 3- methyl-
4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- bases) -1H- indoles obtains as appropriate boronic acid derivatives
The mixture of diastereoisomer.They are by preparative reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution (pH=4,
Adjusted using AcOH) and acetonitrile as eluent.HRMS C26H24N4O2S calculated values：456.1620, measured value：457.1691(M
+H)
Obtain embodiment 86, the diastereoisomer eluted after being.HRMS C26H24N4O2S calculated values：456.1620, it is real
Measured value：457.1688(M+H)
Embodiment 87：N- [6- ethyls -5- (1- methyl isophthalic acid H- indazole -4- bases) thieno [2,3-d] pyrimidine-4-yl]-D-
Phenylalanine
Using universal method IIa, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 1- methyl-
4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- bases) indazole as appropriate boronic acid derivatives, is implemented
Example 87, it is the mixture of diastereoisomer.HRMS C25H23N5O2S calculated values：457.1572, measured value：458.1646 and
458.1648(M+H)
Embodiment 88：N- [6- ethyls-(5Sa) -5- (1- methyl isophthalic acid H- indazole -7- bases) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
With
Embodiment 89：N- [6- ethyls-(5Ra) -5- (1- methyl isophthalic acid H- indazole -7- bases) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
Using universal method IIa, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, (1- methyl
Indazole -7- bases) boric acid as appropriate boronic acid derivatives, obtains embodiment 88, for the diastereoisomer more early eluted.HRMS
C25H23N2O2S calculated values：457.1572, measured value：458.1641(M+H)
Obtain embodiment 89, the diastereoisomer eluted after being.HRMS C25H23N2O2S calculated values：457.1572, it is real
Measured value：458.1634(M+H)
Embodiment 90：N-[(5Sa) simultaneously [2,3-d] is phonetic for -6- ethylthiophenes by -5- (3- chloro -4- hydroxy-2-methyls phenyl)
Pyridine -4- bases]-D-phenylalanine
With
Embodiment 91：N-[(5Ra) simultaneously [2,3-d] is phonetic for -6- ethylthiophenes by -5- (3- chloro -4- hydroxy-2-methyls phenyl)
Pyridine -4- bases]-D-phenylalanine
By 500mg prepare 7e (1.12mMol) and 157mg NCS (1.173mMol) be dissolved in 30mL THF, by mixture in
60 DEG C are stirred overnight.Solvent is evaporated under reduced pressure, residue, using heptane and EtOAc as eluent, is obtained by purification by flash chromatography
2- [[5- (3- chloros -4- hydroxy-2-methyls-phenyl) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl] amino] -3- benzene
Base-methyl propionate, it is the mixture of diastereoisomer (with other region isomers).Crude material is according to universal method
VII is hydrolyzed.Diastereoisomer is by preparative Reverse phase chromatography and separation, using 25mM NH4HCO3The aqueous solution and acetonitrile
As eluent.Obtain embodiment 90, the diastereoisomer eluted after being.HRMS C24H22ClN3O3S calculated values：
467.1070, measured value：468.1153(M+H)
Embodiment 91 is obtained, for the diastereoisomer more early eluted.HRMS C24H22ClN3O3S calculated values：
467.1070, measured value：468.1143(M+H)
Embodiment 92：N-[(5Ra) -5- (2,3- dichloro-s phenyl) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl]-D-
Phenylalanine
With
Embodiment 93：N-[(5Sa) -5- (2,3- dichloro-s phenyl) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl]-D-
Phenylalanine
Using universal method IIa, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, (2,3- bis-
Chlorophenyl) boric acid as appropriate boronic acid derivatives, replaced using XantphosnBuPAd2, obtain the mixed of diastereoisomer
Compound.They, using the 0.1%TFA aqueous solution and acetonitrile as eluent, obtain embodiment by preparative reversed phase chromatography separation
92, for the diastereoisomer more early eluted.HRMS C23H19Cl2N3O2S calculated values：471.0575, measured value：472.0667
(M+H)
Obtain embodiment 93, the diastereoisomer eluted after being.HRMS C23H19Cl2N3O2S calculated values：471.0575
Measured value：472.0654(M+H)
Embodiment 94：N-[(5Ra) -5- (3,4- dichloro- -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -
4- yls]-D-phenylalanine
With
Embodiment 95：N-[(5Sa) -5- (3,4- dichloro- -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -
4- yls]-D-phenylalanine
Using universal method IIb, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, (3,4- bis-
Chloro -2- methylphenyls) as appropriate boronic acid derivatives, Q-Phos, DME are replaced using Xantphos boric acid as part:
Water 4:1 replaces 2-Me-THF, obtains the mixture of diastereoisomer.They are used by preparative reversed phase chromatography separation
The 0.1%TFA aqueous solution and acetonitrile obtain embodiment 94, for the diastereoisomer more early eluted as eluent.HRMS
C24H21Cl2N3O2S calculated values：485.0731, measured value：486.0816(M+H)
Obtain embodiment 95, the diastereoisomer eluted after being.HRMS C24H21Cl2N3O2S calculated values：485.0731
Measured value：486.0797(M+H)
Embodiment 96：N-[(5Ra) -5- (the bromo- 2- aminomethyl phenyls of 3-) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl] -
D-phenylalanine
With
Embodiment 97：N-[(5Sa) -5- (the bromo- 2- aminomethyl phenyls of 3-) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl] -
D-phenylalanine
Using universal method IIa, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, B7 is prepared and makees
For appropriate boronic acid derivatives, the mixture of diastereoisomer is obtained.They are used by preparative reversed phase chromatography separation
40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Embodiment 96 is obtained, for relatively early elution
Diastereoisomer.HRMS C24H22BrN3O2S calculated values：495.0616, measured value：496.0673(M+H)
Obtain embodiment 97, the diastereoisomer eluted after being.HRMS C24H22BrN3O2S calculated values：495.0616
Measured value：496.0687(M+H)
Embodiment 98：N- [6- ethyls -5- (1H- indazole -4- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
Using universal method IIa, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 1H- indazoles-
4- ylboronic acids are as appropriate boronic acid derivatives, then by preparative Reverse phase chromatography crude material, using 0.1%TFA
The aqueous solution and acetonitrile obtain embodiment 98, are the mixture of diastereoisomer as eluent.HRMS C24H21N5O2S is calculated
Value：443.1416, measured value：444.1485 with 444.1481 (M+H)
Embodiment 99：N- [6- ethyls -5- (quinoline-8-yl) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
Using universal method IId, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, 8- quinolyls
Boric acid obtains embodiment 99, is the mixture of diastereoisomer as appropriate boronic acid derivatives.HRMS C26H28N4O2S is counted
Calculation value：454.1463, measured value：455.1558(M+H)
Embodiment 100：N- [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid
With
Embodiment 101：N- [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid
Using the diastereoisomer of preparative reversed phase chromatography separation embodiment 79, using the 0.1%TFA aqueous solution and acetonitrile
As eluent, embodiment 100 is obtained, for the diastereoisomer more early eluted.HRMS C27H23N3O2S calculated values：
453.1511, measured value：454.1596(M+H)
Obtain embodiment 101, the diastereoisomer eluted after being.HRMS C27H23N3O2S calculated values：453.1511, it is real
Measured value：454.1577(M+H)
Embodiment 102：N- [6- vinyl-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohols
Propylhomoserin
With
Embodiment 103：N- [6- vinyl-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohols
Propylhomoserin
Using universal method Ia, 4w is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains embodiment 102, for the diastereoisomer more early eluted as appropriate amino acid derivativges.HRMS
C27H21N3O2S calculated values：451.1354, measured value：452.1411(M+H)
Obtain embodiment 103, the diastereoisomer eluted after being.HRMS C27H21N3O2S calculated values：451.1354, it is real
Measured value：452.1412(M+H)
Embodiment 104：N-[(5Sa) -5- (naphthalene -1- bases) -6- ((1Z) -propyl- 1- alkene -1- bases) thieno [2,3-d] is phonetic
Pyridine -4- bases]-D-phenylalanine
With
Embodiment 105：N-[(5Ra) -5- (naphthalene -1- bases) -6- ((1Z) -propyl- 1- alkene -1- bases) thieno [2,3-d] is phonetic
Pyridine -4- bases]-D-phenylalanine
Using universal method Ib, 4x is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Embodiment 104 is obtained, is
The diastereoisomer more early eluted.HRMS C28H23N3O2S calculated values：465.1511, measured value：466.1577(M+H)
Embodiment 104 also includes 55% embodiment 108.
Obtain embodiment 105, the diastereoisomer eluted after being.HRMS C28H23N3O2S calculated values：465.1511, it is real
Measured value：466.1578(M+H)
Embodiment 105 also includes 55% embodiment 109.
Embodiment 106：N-[(5Sa) -5- (naphthalene -1- bases) -6- (propyl- 1- alkene -2- bases) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
With
Embodiment 107：N-[(5Ra) -5- (naphthalene -1- bases) -6- (propyl- 1- alkene -2- bases) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
Using universal method Ia, 4y is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Embodiment 106 is obtained, is
The diastereoisomer more early eluted.HRMS C28H23N3O2S calculated values：465.1511, measured value：466.1581(M+H)
Obtain embodiment 107, the diastereoisomer eluted after being.HRMS C28H23N3O2S calculated values：465.1511, it is real
Measured value：466.1597(M+H)
Embodiment 108：N-{(5Sa) -5- (naphthalene -1- bases) -6- [(1E) -propyl- 1- alkene -1- bases] thieno [2,3-d] is phonetic
Pyridine -4- bases }-D-phenylalanine
With
Embodiment 109：N-{(5Ra) -5- (naphthalene -1- bases) -6- [(1E) -propyl- 1- alkene -1- bases] thieno [2,3-d] is phonetic
Pyridine -4- bases }-D-phenylalanine
Using universal method Ia, 4z is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Embodiment 108 is obtained, is
The diastereoisomer more early eluted.HRMS C28H23N3O2S calculated values：465.1511, measured value：466.1593(M+H)
Obtain embodiment 109, the diastereoisomer eluted after being.HRMS C28H23N3O2S calculated values：465.1511, it is real
Measured value：466.1581(M+H)
Embodiment 110：N- [5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl] -3-
(1H- pyrazol-1-yls) alanine
Using universal method Ic, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, 2- amino-
Then 3- pyrazol-1-yls-propionate hydrochloride is hydrolyzed and formed according to universal method VII as appropriate amino acid derivativges
Intermediate, obtain the mixture of diastereoisomer.It is water-soluble using 0.1%TFA by it by preparative Reverse phase chromatography
Liquid and acetonitrile obtain embodiment 110, are non-enantiomer mixture as eluent.HRMS C21H20ClN5O2S calculated values：
441.1026, measured value：442.1120 with 442.1123 (M+H)
Embodiment 111：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -3- cyclopenta-D-alanine
With
Embodiment 112：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -3- cyclopenta-D-alanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- cyclopenta-propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through system
Standby property reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 111 is obtained, for relatively early elution
Diastereoisomer.HRMS C23H26ClN3O2S calculated values：443.1434, measured value：444.1519(M+H)
Obtain embodiment 112, the diastereoisomer eluted after being.HRMS C23H26ClN3O2S calculated values：443.1434
Measured value：444.1518(M+H)
Embodiment 113：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
With
Embodiment 114：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
Using universal method IIa, 3a is prepared as the appropriate iodo- thienos of 5- [2,3-d] pyrimidine derivatives, (3- chloros-
2- methylphenyls) boric acid as appropriate boronic acid derivatives, obtains the mixture of diastereoisomer.They pass through preparative
Reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Obtain real
Example 113 is applied, for the diastereoisomer more early eluted.HRMS C24H22ClN3O2S calculated values：451.1121, measured value：
452.1192(M+H)
Obtain embodiment 114, the diastereoisomer eluted after being.HRMS C24H22ClN3O2S calculated values：451.1121
Measured value：452.1174(M+H)
Embodiment 115：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base]-L-phenylalanine
With
Embodiment 116：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base]-L-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, L- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using the 0.1%TFA aqueous solution and acetonitrile as eluent.Obtain
Embodiment 115, for the diastereoisomer more early eluted.HRMS C24H22ClN3O2S calculated values：451.1121, it is real
Measured value：452.1207(M+H)
Obtain embodiment 116, the diastereoisomer eluted after being.HRMS C24H22ClN3O2S calculated values：451.1121
Measured value：452.1183(M+H)
Embodiment 117：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -3- cyclohexyl-D-alanine
With
Embodiment 118：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -3- cyclohexyl-D-alanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- cyclohexyl-propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through system
Standby property reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 117 is obtained, for relatively early elution
Diastereoisomer.HRMS C24H28ClN3O2S calculated values：457.1591, measured value：458.1672(M+H)
Obtain embodiment 118, the diastereoisomer eluted after being.HRMS C24H28ClN3O2S calculated values：457.1591
Measured value：458.1663(M+H)
Embodiment 119：N- [5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine-4-yl]-α-first
Base-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino-2-methyl -3- phenyl-propionics obtain the mixture of diastereoisomer as appropriate amino acid derivativges.Led to
Preparative Reverse phase chromatography is crossed, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 119 is obtained, is non-right
Reflect the mixture of isomers.HRMS C25H24ClN3O2S calculated values：465.1278, measured value：466.1372 with 466.1356 (M+
H)
Embodiment 120：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- hydroxyls-D-phenylalanine
With
Embodiment 121：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- hydroxyls-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- hydroxy phenyls) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They are logical
Preparative reversed phase chromatography separation is crossed, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 120 is obtained, is more early
The diastereoisomer of elution.HRMS C24H22ClN3O3S calculated values：467.1070, measured value：468.1135(M+H)
Obtain embodiment 121, the diastereoisomer eluted after being.HRMS C24H22ClN3O3S calculated values：467.1070
Measured value：468.1162(M+H)
Embodiment 122：(βS)-N-[(5Ra) simultaneously [2,3-d] is phonetic for -6- ethylthiophenes by -5- (3- chloro -2- aminomethyl phenyls)
Pyridine -4- bases]-beta-hydroxy-D-phenylalanine
With
Embodiment 123：(βS)-N-[(5Sa) simultaneously [2,3-d] is phonetic for -6- ethylthiophenes by -5- (3- chloro -2- aminomethyl phenyls)
Pyridine -4- bases]-beta-hydroxy-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R,
3S) -3- Phenserines obtain the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparation
Property reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.
Embodiment 122 is obtained, for the diastereoisomer more early eluted.HRMS C24H22ClN3O3S calculated values：
467.1070, measured value：468.1151(M+H)
Obtain embodiment 123, the diastereoisomer eluted after being.HRMS C24H22ClN3O3S calculated values：467.1070
Measured value：468.1133(M+H)
Embodiment 124：(βR)-N-[(5Ra) simultaneously [2,3-d] is phonetic for -6- ethylthiophenes by -5- (3- chloro -2- aminomethyl phenyls)
Pyridine -4- bases]-beta-hydroxy-L-phenylalanine
With
Embodiment 125：(βR)-N-[(5Sa) simultaneously [2,3-d] is phonetic for -6- ethylthiophenes by -5- (3- chloro -2- aminomethyl phenyls)
Pyridine -4- bases]-beta-hydroxy-L-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2S,
3R) -2- amino -3- hydroxyl -3- phenylpropionic acids obtain the mixture of diastereoisomer as appropriate amino acid derivativges.
They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 124 is obtained,
For the diastereoisomer more early eluted.HRMS C24H22ClN3O3S calculated values：467.1070, measured value：468.1144(M+H)
Obtain embodiment 125, the diastereoisomer eluted after being.HRMS C24H22ClN3O3S calculated values：467.1070
Measured value：468.1153(M+H)
Embodiment 126：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- cyano group-D-phenylalanine
With
Embodiment 127N- [(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- cyano group-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- cyano-phenyls) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They are logical
Preparative reversed phase chromatography separation is crossed, is obtained using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 126, it is more early
The diastereoisomer of elution.HRMS C25H21ClN4O2S calculated values：476.1074, measured value：477.1129(M+H)
Obtain embodiment 127, the diastereoisomer eluted after being.HRMS C25H21ClN4O2S calculated values：476.1074
Measured value：477.1134(M+H)
Embodiment 128：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- methoxyl groups-D-phenylalanine
With
Embodiment 129：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- methoxyl groups-D-phenylalanine
Using universal method Ic, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- methoxyphenyls) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They
By preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Obtain embodiment 128, be compared with
The diastereoisomer early eluted.HRMS C25H24ClN3O3S calculated values：481.1227, measured value：482.1320(M+H)
Obtain embodiment 129, the diastereoisomer eluted after being.HRMS C25H24ClN3O3S calculated values：481.1227
Measured value：482.1319(M+H)
Embodiment 130：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] two fluoro- D-phenylalanines of -2,6-
With
Embodiment 131：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] two fluoro- D-phenylalanines of -2,6-
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2,6- difluorophenyl) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They
By preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Obtain embodiment 130, be compared with
The diastereoisomer early eluted.HRMS C24H20ClF2N3O2S calculated values：487.0933, measured value：488.1009(M+H)
Obtain embodiment 131, the diastereoisomer eluted after being.HRMS C24H20ClF2N3O2S calculated values：
487.0933, measured value：488.1020(M+H)
Embodiment 132：(2R)-2-{[(5Ra) simultaneously [2,3-d] is phonetic for -6- ethylthiophenes by -5- (3- chloro -2- aminomethyl phenyls)
Pyridine -4- bases] amino } -3- (1H- indoles -4- bases) propionic acid
With
Embodiment 133：(2R)-2-{[(5Sa) simultaneously [2,3-d] is phonetic for -6- ethylthiophenes by -5- (3- chloro -2- aminomethyl phenyls)
Pyridine -4- bases] amino } -3- (1H- indoles -4- bases) propionic acid
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (1H- indoles -4- bases) propionate hydrochlorate as appropriate amino acid derivativges, obtains the mixing of diastereoisomer
Thing.They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Obtain embodiment
132, for the diastereoisomer more early eluted.HRMS C26H23ClN4O2S calculated values：490.1230, measured value：491.1289
(M+H)
Obtain embodiment 133, the diastereoisomer eluted after being.HRMS C26H23ClN4O2S calculated values：490.1230
Measured value：491.1309(M+H)
Embodiment 134：2- carbamoyl-N- [(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,
3-d] pyrimidine-4-yl]-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- Carbamoylphenyls) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.
They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 134 is obtained,
For the diastereoisomer of rear elution.HRMS C25H23ClN4O3S calculated values：494.1179, measured value：495.1255(M+H)
Embodiment 135：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- nitros-D-phenylalanine
With
Embodiment 136：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- nitros-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- nitrobenzophenones) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They are logical
Preparative reversed phase chromatography separation is crossed, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 135 is obtained, is more early
The diastereoisomer of elution.HRMS C24H21ClN4O4S calculated values：496.0972, measured value：497.1026(M+H)
Obtain embodiment 136, the diastereoisomer eluted after being.HRMS C24H21ClN4O4S calculated values：496.0972
Measured value：497.1045(M+H)
Embodiment 137：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- (trifluoromethyl)-D-phenylalanine
With
Embodiment 138：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- (trifluoromethyl)-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- [2- (trifluoromethyl) phenyl] propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.
They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 137 is obtained,
For the diastereoisomer more early eluted.HRMS C25H21ClF3N3O2S calculated values：519.0995, measured value：520.1068(M+
H)
Obtain embodiment 138, the diastereoisomer eluted after being.HRMS C25H21ClF3N3O2S calculated values：
519.0995, measured value：520.1047(M+H)
Embodiment 139：Bromo- the N- [(5R of 2-a) simultaneously [2,3-d] is phonetic for -6- ethylthiophenes by -5- (3- chloro -2- aminomethyl phenyls)
Pyridine -4- bases]-D-phenylalanine
With
Embodiment 140：Bromo- the N- [(5S of 2-a) simultaneously [2,3-d] is phonetic for -6- ethylthiophenes by -5- (3- chloro -2- aminomethyl phenyls)
Pyridine -4- bases]-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- [2- bromophenyls] propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through
Preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 139 is obtained, is washed to be relatively early
De- diastereoisomer.HRMS C24H21ClBrN3O2S calculated values：529.0226, measured value：530.0312(M+H)
Obtain embodiment 140, the diastereoisomer eluted after being.HRMS C24H21ClBrN3O2S calculated values：
529.0226, measured value：530.0294(M+H)
Embodiment 141：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- [2- (dimethylamino) -2- oxoethoxies]-D-phenylalanine
With
Embodiment 142：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- [2- (dimethylamino) -2- oxoethoxies]-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A9
As appropriate amino acid derivativges, the mixture of diastereoisomer is obtained.They are adopted by preparative reversed phase chromatography separation
Eluent is used as by the use of the 0.1%TFA aqueous solution and acetonitrile.Embodiment 141 is obtained, for the diastereoisomer more early eluted.HRMS
C28H29ClN4O4S calculated values：552.1598, measured value：553.1694(M+H)
Obtain embodiment 142, the diastereoisomer eluted after being.HRMS C28H29ClN4O4S calculated values：552.1598
Measured value：553.1673(M+H)
Embodiment 143：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- (2- cyclopenta ethyoxyl)-D-phenylalanine
With
Embodiment 144：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- (2- cyclopenta ethyoxyl)-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A10
As appropriate amino acid derivativges, the mixture of diastereoisomer is obtained.They are adopted by preparative reversed phase chromatography separation
Eluent is used as by the use of the 0.1%TFA aqueous solution and acetonitrile.Embodiment 143 is obtained, for the diastereoisomer more early eluted.HRMS
C31H34ClN3O3S calculated values：563.2009, measured value：564.2106(M+H)
Obtain embodiment 144, the diastereoisomer eluted after being.HRMS C31H34ClN3O3S calculated values：563.2009
Measured value：564.2101(M+H)
Embodiment 145：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- (2- phenyl ethoxies)-D-phenylalanine
With
Embodiment 146：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- (2- phenyl ethoxies)-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A11
As appropriate amino acid derivativges, the mixture of diastereoisomer is obtained.They are adopted by preparative reversed phase chromatography separation
Eluent is used as by the use of the 0.1%TFA aqueous solution and acetonitrile.Embodiment 145 is obtained, for the diastereoisomer more early eluted.HRMS
C32H30ClN3O3S calculated values：571.1696, measured value：572.1769(M+H)
Obtain embodiment 146, the diastereoisomer eluted after being.HRMS C32H30ClN3O3S calculated values：571.1696
Measured value：572.1763(M+H)
Embodiment 147：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- (3- phenyl-propoxies)-D-phenylalanine
With
Embodiment 148：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- (3- phenyl-propoxies)-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A12
As appropriate amino acid derivativges, the mixture of diastereoisomer is obtained.They are adopted by preparative reversed phase chromatography separation
Eluent is used as by the use of the 0.1%TFA aqueous solution and acetonitrile.Embodiment 147 is obtained, for the diastereoisomer more early eluted.HRMS
C33H32ClN3O3S calculated values：585.1853, measured value：586.1917(M+H)
Obtain embodiment 148, the diastereoisomer eluted after being.HRMS C33H32ClN3O3S calculated values：585.1853
Measured value：586.1906(M+H)
Embodiment 149：2- [(3- chlorobenzyls) epoxide]-N- [(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethyls
Thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
With
Embodiment 150：2- [(3- chlorobenzyls) epoxide]-N- [(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethyls
Thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A13
As appropriate amino acid derivativges, the mixture of diastereoisomer is obtained.They are adopted by preparative reversed phase chromatography separation
Eluent is used as by the use of the 0.1%TFA aqueous solution and acetonitrile.Embodiment 149 is obtained, for the diastereoisomer more early eluted.HRMS
C31H27Cl2N3O3S calculated values：591.1150, measured value：592.1211(M+H)
Obtain embodiment 150, the diastereoisomer eluted after being.HRMS C31H27Cl2N3O3S calculated values：
591.1150, measured value：592.1234(M+H)
Embodiment 151：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -3- pyridines -2- bases-D-alanine
With
Embodiment 152：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -3- pyridines -2- bases-D-alanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- pyridine radicals) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through
Preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 151 is obtained, is washed to be relatively early
De- diastereoisomer.HRMS C23H21ClN4O2S calculated values：452.1074, measured value：453.1146(M+H)
Obtain embodiment 15, the diastereoisomer eluted after being.HRMS C23H21ClN4O2S calculated values：452.1074
Measured value：453.1135(M+H)
Embodiment 153：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- [2- (4- methylpiperazine-1-yls) ethyoxyl]-D-phenylalanine
With
Embodiment 154：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- [2- (4- methylpiperazine-1-yls) ethyoxyl]-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A14
As appropriate amino acid derivativges, the mixture of diastereoisomer is obtained.They are adopted by preparative reversed phase chromatography separation
Eluent is used as by the use of the 0.1%TFA aqueous solution and acetonitrile.
Embodiment 153 is obtained, for the diastereoisomer more early eluted.HRMS C31H36ClN5O3S calculated values：
593.2227, measured value：594.2297(M+H)
Obtain embodiment 154, the diastereoisomer eluted after being.HRMS C31H36ClN5O3S calculated values：593.2227
Measured value：594.2289(M+H)
Embodiment 155：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- [2- (dimethylamino) ethyoxyl]-D-phenylalanine
With
Embodiment 156：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- [2- (dimethylamino) ethyoxyl]-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A15
As appropriate amino acid derivativges, the mixture of diastereoisomer is obtained.They are adopted by preparative reversed phase chromatography separation
Eluent is used as by the use of the 0.1%TFA aqueous solution and acetonitrile.
Embodiment 155 is obtained, for the diastereoisomer more early eluted.HRMS C28H31ClN4O3S calculated values：
538.1805, measured value：539.1890(M+H)
Obtain embodiment 156, the diastereoisomer eluted after being.HRMS C28H31ClN4O3S calculated values：538.1805
Measured value：539.1887(M+H)
Embodiment 157：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- [3- (dimethylamino) propoxyl group]-D-phenylalanine
With
Embodiment 158：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base] -2- [3- (dimethylamino) propoxyl group]-D-phenylalanine
Using universal method Ib, 4j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, prepares A16
As appropriate amino acid derivativges, the mixture of diastereoisomer is obtained.They are adopted by preparative reversed phase chromatography separation
Eluent is used as by the use of the 0.1%TFA aqueous solution and acetonitrile.
Embodiment 157 is obtained, for the diastereoisomer more early eluted.HRMS C29H33ClN4O3S calculated values：
552.1962, measured value：553.2043(M+H)
Obtain embodiment 158, the diastereoisomer eluted after being.HRMS C29H33ClN4O3S calculated values：552.1962
Measured value：553.2053(M+H).
Embodiment 159：3- cyclopropyl-N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- third
Propylhomoserin
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- cyclopropyl-propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through system
Standby property reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 159 is obtained, is that diastereomeric is different
Structure body mixture.HRMS C24H23N3O2S calculated values：417.1511, measured value：418.1570(M+H)
Embodiment 160：(2R)-{ [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] amino } (phenyl)
Acetic acid, diastereoisomer 1
With
Embodiment 161：(2R)-{ [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] amino } (phenyl)
Acetic acid, diastereoisomer 2
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -2- phenyl-acetic acids replace DMSO as solvent using DMA, obtain diastereo-isomerism as appropriate amino acid derivativges
The mixture of body.They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Obtain
Embodiment 160, for the diastereoisomer more early eluted.HRMS C26H21N3O2S calculated values：439.1354, measured value：
440.1428(M+H)
Obtain embodiment 161, the diastereoisomer eluted after being.HRMS C26H21N3O2S calculated values：439.1354, it is real
Measured value：440.1412(M+H)
Embodiment 162：N- [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -3- pyridines -
3- bases-D-alanine
With
Embodiment 163：N- [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -3- pyridines -
3- bases-D-alanine
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (3- pyridine radicals) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through
Preparative reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.
Embodiment 162 is obtained, for the diastereoisomer more early eluted.HRMS C26H22N4O2S calculated values：454.1463, measured value：
455.1520(M+H)
Obtain embodiment 163, the diastereoisomer eluted after being.HRMS C26H22N4O2S calculated values：454.1463, it is real
Measured value：455.1536(M+H)
Embodiment 164：3- cyclohexyl-N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- third
Propylhomoserin
Using universal method Ia, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- cyclohexyl-propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.Passed through system
Standby property Reverse phase chromatography, using the 0.02%HCOOH aqueous solution and acetonitrile as eluent.Embodiment 164 is obtained, is diastereomeric
Isomer mixture.HRMS C27H29N3O2S calculated values：459.1980, measured value：460.2042(M+H)
Embodiment 165：3- cyclohexyl-N- [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidines -4-
Base]-D-alanine
With
Embodiment 166：3- cyclohexyl-N- [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidines -4-
Base]-D-alanine
By the diastereoisomer of preparative reversed phase chromatography separation embodiment 164, using 40mM NH4The OAc aqueous solution
(pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Embodiment 165 is obtained, for the diastereoisomer more early eluted.
HRMS C27H29N3O2S calculated values：459.1980, measured value：460.2043(M+H)
Obtain embodiment 166, the diastereoisomer eluted after being.HRMS C27H29N3O2S calculated values：459.1980, it is real
Measured value：460.2058(M+H)
Embodiment 167：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- methyl Ds-phenylpropyl alcohol
Propylhomoserin, diastereoisomer 1
With
Embodiment 168：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- methyl Ds-phenylpropyl alcohol
Propylhomoserin, diastereoisomer 2
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D-2 '-first
Base phenylalanine obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They are anti-phase by preparative
Chromatographic isolation, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Obtain embodiment
167, for the diastereoisomer more early eluted.HRMS C28H25N3O2S calculated values：467.1667, measured value：468.1747(M+
H)
Obtain embodiment 168, the diastereoisomer eluted after being.HRMS calculated values C28H25N3O2S：467.1667, it is real
Measured value：468.1748(M+H)
Embodiment 169：(2R) -2- { [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] amino } -4-
Phenylbutyric acid
Using universal method Ia, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino-4-phenyl-butyric acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.Passed through preparation
Property Reverse phase chromatography, using the 0.02%HCOOH aqueous solution and acetonitrile as eluent.Embodiment 169 is obtained, is that diastereomeric is different
The mixture of structure body.HRMS C28H25N3O2S calculated values：467.1667, measured value：468.1731(M+H)
Embodiment 170：(2R) -2- { [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] ammonia
Base } -4-phenylbutyrate
With
Embodiment 171：(2R) -2- { [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] ammonia
Base } -4-phenylbutyrate
The diastereoisomer of embodiment 169 is by preparative reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution
(pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Embodiment 170 is obtained, for the diastereoisomer more early eluted.
HRMS C28H25N3O2S calculated values：467.1667, measured value：468.1733(M+H)
Obtain embodiment 171, the diastereoisomer eluted after being.HRMS C28H25N3O2S calculated values：467.1667, it is real
Measured value：468.1726(M+H)
Embodiment 172：N- [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-Tyrosine
With
Embodiment 173：N- [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-Tyrosine
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (4- hydroxy phenyls) propionic acid replaces DMSO as solvent using DMA, obtained non-as appropriate amino acid derivativges
The mixture of enantiomter.They are used as using the 0.1%TFA aqueous solution and acetonitrile and washed by preparative reversed phase chromatography separation
De- liquid.
Embodiment 172 is obtained, for the diastereoisomer more early eluted.HRMS C27H23N3O3S calculated values：469.1460
Measured value：470.1539(M+H)
Obtain embodiment 173, the diastereoisomer eluted after being.HRMS C27H23N3O3S calculated values：469.1460, it is real
Measured value：470.1534(M+H)
Embodiment 174：N- [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- hydroxyls -
D-phenylalanine
With
Embodiment 175：N- [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- hydroxyls -
D-phenylalanine
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- hydroxy phenyls) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They are logical
Preparative reversed phase chromatography separation is crossed, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as elution
Liquid.
Embodiment 174 is obtained, for the diastereoisomer more early eluted.HRMS C27H23N3O3S calculated values：469.1460
Measured value：470.1546(M+H)
Obtain embodiment 175, the diastereoisomer eluted after being.HRMS C27H23N3O3S calculated values：469.1460, it is real
Measured value：470.1520(M+H)
Embodiment 176：N- [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] the fluoro- D- of -4-
Phenylalanine
With
Embodiment 177：N- [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] the fluoro- D- of -4-
Phenylalanine
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (4- fluorophenyls) propionic acid replaces DMSO, it is non-right to obtain using DMA as appropriate amino acid derivativges as solvent
Reflect the mixture of isomers.They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as elution
Liquid.
Embodiment 176 is obtained, for the diastereoisomer more early eluted.HRMS C27H22FN3O2S calculated values：
471.1417, measured value：472.1493(M+H)
Obtain embodiment 177, the diastereoisomer eluted after being.HRMS C27H22FN3O2S calculated values：471.1417
Measured value：472.1494(M+H)
Embodiment 178：N- [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] the fluoro- D- of -3-
Phenylalanine
With
Embodiment 179：N- [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] the fluoro- D- of -3-
Phenylalanine
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (3- fluorophenyls) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through
Preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.
Embodiment 178 is obtained, for the diastereoisomer more early eluted.HRMS C27H22FN3O2S calculated values：
471.1417, measured value：472.1486(M+H)
Obtain embodiment 179, the diastereoisomer eluted after being.HRMS C27H22FN3O2S calculated values：471.1417
Measured value：472.1482(M+H)
Embodiment 180：N- [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] the fluoro- D- of -2-
Phenylalanine
With
Embodiment 181：N- [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] the fluoro- D- of -2-
Phenylalanine
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- fluorophenyls) propionic acid replaces DMSO, it is non-right to obtain using DMA as appropriate amino acid derivativges as solvent
Reflect the mixture of isomers.They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as elution
Liquid.
Embodiment 180 is obtained, for the diastereoisomer more early eluted.HRMS C27H22FN3O2S calculated values：
471.1417, measured value：472.1501(M+H)
Obtain embodiment 181, the diastereoisomer eluted after being.HRMS C27H22FN3O2S calculated values：471.1417
Measured value：472.1492(M+H)
Embodiment 182：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl group-D- benzene
Alanine
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- methoxyphenyls) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.By its
By preparative Reverse phase chromatography, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile, which are used as, to be washed
De- liquid.Embodiment 182 is obtained, is the mixture of diastereoisomer.HRMS C28H25N3O3S calculated values：483.1617, actual measurement
Value：484.1682 with 484.1695 (M+H)
Embodiment 183：2- chloros-N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohols
Propylhomoserin
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- chlorophenyls) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.Led to
Preparative Reverse phase chromatography is crossed, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 183 is obtained, is non-right
Reflect isomer mixture.HRMS C27H22ClN3O2S calculated values：487.1121, measured value：488.1198 with 488.1199 (M+H)
Embodiment 184：N- [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-trp
With
Embodiment 185：N- [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-trp
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (1H- indol-3-yls) propionic acid replaces DMSO as solvent using DMA, obtained as appropriate amino acid derivativges
The mixture of diastereoisomer.They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile conduct
Eluent.Embodiment 184 is obtained, for the diastereoisomer more early eluted.HRMS C29H24N4O2S calculated values：492.1620
Measured value：493.1693(M+H)
Obtain embodiment 185, the diastereoisomer eluted after being.HRMS C29H24N4O2S calculated values：492.1620, it is real
Measured value：493.1690(M+H)
Embodiment 186：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -3- naphthalene -1- bases-D- third
Propylhomoserin, diastereoisomer 1
With
Embodiment 187：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -3- naphthalene -1- bases-D- third
Propylhomoserin, diastereoisomer 2
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (1- naphthyls) propionic acid replaces DMSO as solvent using DMA, obtains diastereomeric as appropriate amino acid derivativges
The mixture of isomers.They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.
Embodiment 186 is obtained, for the diastereoisomer more early eluted.HRMS C31H25N3O2S calculated values：503.1667, measured value：
504.1754(M+H)
Obtain embodiment 187, the diastereoisomer eluted after being.HRMS C31H25N3O2S calculated values：503.1667, it is real
Measured value：504.1758(M+H)
Embodiment 188：(2R)-biphenyl -2- bases { [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] ammonia
Base } acetic acid, diastereoisomer 2
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (R)-ammonia
Base-biphenyl -2- bases-acetic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparation
Property reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Obtain
Embodiment 188, the diastereoisomer eluted after being.HRMS C32H25N3O2S calculated values：515.1667, measured value：
516.1747(M+H)
Embodiment 189：(2R)-biphenyl -3- bases { [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] ammonia
Base } acetic acid, diastereoisomer 1
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (R)-ammonia
Base-biphenyl -3- bases-acetic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparation
Property reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Obtain
Embodiment 189, for the diastereoisomer more early eluted.HRMS C32H25N3O2S calculated values：515.1667, measured value：
516.1743(M+H)
Embodiment 190：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-His
Using universal method Ia, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (1H- imidazol-4 yls) propionic acid is as appropriate amino acid derivativges, the mixture of diastereoisomer.Passed through
Preparative Reverse phase chromatography, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 190 is obtained, is diastereomeric
The mixture of isomers.HRMSC24H21N5O2S calculated values：443.1416, measured value：444.1462 with 444.1471, two kinds non-
Enantiomter s (M+H)
Embodiment 191：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -3- pyridine -2- bases-D-
Alanine
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- pyridine radicals) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.Passed through
Preparative Reverse phase chromatography, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 191 is obtained, is diastereomeric
The mixture of isomers.HRMS C26H22N4O2S calculated values：454.1463, measured value：455.1537 with 455.1558, two kinds non-
Enantiomter (M+H)
Embodiment 192：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -3- pyridin-3-yls-D-
Alanine
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, 3- (3- pyrroles
Piperidinyl)-D-alanine as appropriate amino acid derivativges, obtains the mixture of diastereoisomer.Passed through preparative
Reverse phase chromatography, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 192 is obtained, is diastereoisomer
Mixture.HRMS C26H22N4O2S calculated values：454.1445, measured value：455.1545 and 455.1553, two kinds of diastereomeric are different
Structure body (M+H)
Embodiment 193：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -3- pyridin-4-yls-D-
Alanine
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (4- pyridine radicals) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.Passed through
Preparative Reverse phase chromatography, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 193 is obtained, is diastereomeric
The mixture of isomers.HRMSC26H22N4O2S calculated values：454.1440, measured value：455.1540 with 455.1545, two kinds non-
Enantiomter (M+H)
Embodiment 194：N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -1- methyl Ds-group ammonia
Acid
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (1- methylimidazole -4- bases) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.
By it by preparative Reverse phase chromatography, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 194 is obtained,
For the mixture of diastereoisomer.HRMSC25H23N5O2S calculated values：457.1572, measured value：458.1641 and
458.1654, two kinds of diastereoisomer s (M+H)
Embodiment 195：1- benzyls-N- [6- ethyls -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- organizes ammonia
Acid
Using universal method Ib, 4k is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (1- benzyl imidazole -4- bases) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.
By it by preparative Reverse phase chromatography, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 195 is obtained,
For the mixture of diastereoisomer.HRMS C31H27N5O2S calculated values：533.1885, measured value：534.1934 and
534.1934, two kinds of diastereoisomers (M+H)
Embodiment 196：N- [6- methyl -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
Using universal method Ia, 4l is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.It is pure by preparative reverse-phase chromatography
Change, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Obtain
Embodiment 196, it is the mixture of diastereoisomer.HRMS C26H21N3O2S calculated values：439.1354, actual measurement
Value：440.1421 with 440.1429 (M+H)
Embodiment 197：N- [6- (hydroxymethyl)-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-
Phenylalanine
With
Embodiment 198：N- [6- (hydroxymethyl)-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-
Phenylalanine
Using universal method Ia, 4m is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 197 is obtained, for the diastereoisomer more early eluted.
HRMS C26H21N3O3S calculated values：455.1304, measured value：456.1356(M+H)
Obtain embodiment 198, the diastereoisomer eluted after being.HRMS C26H21N3O3S calculated values：455.1304, it is real
Measured value：456.1390(M+H)
Embodiment 199：N- [6- acetyl group-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohols
Propylhomoserin
With
Embodiment 200：N- [6- acetyl group-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohols
Propylhomoserin
Using universal method Ia, 4o is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Embodiment 199 is obtained, is
The diastereoisomer more early eluted.HRMS C27H21N3O3S calculated values：467.1304, measured value：468.1379(M+H)
Obtain embodiment 200, the diastereoisomer eluted after being.HRMS C27H21N3O3S calculated values：467.1304, it is real
Measured value：468.1377(M+H)
Embodiment 201：N- [5- (naphthalene -1- bases) -6- (propyl- 2- yls) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid, diastereoisomer 1
With
Embodiment 202：N- [5- (naphthalene -1- bases) -6- (propyl- 2- yls) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid, diastereoisomer 2
Using universal method Ib, 4q is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Embodiment 201 is obtained, is
The diastereoisomer more early eluted.HRMS C28H25N3O2S calculated values：467.1667, measured value：468.1731(M+H)
Obtain embodiment 202, the diastereoisomer eluted after being.HRMS C28H25N3O2S calculated values：467.1667, it is real
Measured value：468.1720(M+H)
Embodiment 203：N- [6- (1- hydroxyethyls) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohols
Propylhomoserin, diastereoisomer 1
With
Embodiment 204：N- [6- (1- hydroxyethyls) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohols
Propylhomoserin, diastereoisomer 2
Using universal method Ia, 4n1 is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 203 is obtained, for the diastereoisomer more early eluted.
HRMS C27H23N3O3S calculated values：469.1460, measured value：470.1511(M+H)
Obtain embodiment 204, the diastereoisomer eluted after being.HRMS C27H23N3O3S calculated values：469.1460, it is real
Measured value：470.1536(M+H)
Embodiment 205：N- [6- (1- hydroxyethyls) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohols
Propylhomoserin, diastereoisomer 3
With
Embodiment 206：N- [6- (1- hydroxyethyls) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohols
Propylhomoserin, diastereoisomer 4
Using universal method Ia, 4n2 is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 205 is obtained, for the diastereoisomer more early eluted.
HRMS C27H23N3O3S calculated values：469.1460, measured value：470.1539(M+H)
Obtain embodiment 206, the diastereoisomer eluted after being.HRMS C27H33N3O3S calculated values：469.1460, it is real
Measured value：470.1534(M+H)
Embodiment 207：N- [6- (difluoromethyl) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid, diastereoisomer 1
With
Embodiment 208：N- [6- (difluoromethyl) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid, diastereoisomer 2
Using universal method Ia, 4r is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Embodiment 207 is obtained, is
The diastereoisomer more early eluted.HRMS C26H19F2N3O2S calculated values：475.1166, measured value：476.1242(M+H)
Obtain embodiment 208, the diastereoisomer eluted after being.HRMS C26H19F2N3O2S calculated values：475.1166
Measured value：476.1244(M+H)
Embodiment 209：N- [6- (2- hydroxyl propyl- 2- yls)-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidines -4-
Base]-D-phenylalanine
With
Embodiment 210：N- [6- (2- hydroxyl propyl- 2- yls)-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidines -4-
Base]-D-phenylalanine
Using universal method Ia, 4p is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 209 is obtained, for the diastereoisomer more early eluted.
HRMS C28H25N3O3S calculated values：483.1617, measured value：484.1689(M+H)
Obtain embodiment 210, the diastereoisomer eluted after being.HRMS C28H25N3O3S calculated values：483.1617, it is real
Measured value：484.1704(M+H)
Embodiment 211：N- [the iodo- 5- of 6- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine
Using universal method Ia, 4s is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin replaces DMSO as solvent using DMA, obtains the mixture of diastereoisomer as appropriate amino acid derivativges.
By it by preparative Reverse phase chromatography, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are made
For eluent.Embodiment 211 is obtained, is the mixture of diastereoisomer.HRMS C25H18IN3O2S calculated values：551.0164
Measured value：552.0258(M+H)
Embodiment 212：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- vinyl-thieno [2,3-d] pyrimidine -
4- yls]-D-phenylalanine
With
Embodiment 213：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- vinyl-thieno [2,3-d] pyrimidine -
4- yls]-D-phenylalanine
Using universal method IIc, 5a is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine, where is vinyl boronic acids frequency
Alcohol ester obtains the mixture of diastereoisomer as appropriate boronic acid derivatives.They by preparative reversed phase chromatography separation,
Using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 212 is obtained, for the diastereoisomer more early eluted.
HRMS C24H20ClN3O2S calculated values：449.0965, measured value：450.1038(M+H)
Obtain embodiment 213, the diastereoisomer eluted after being.HRMS C24H20ClN3O2S calculated values：449.0965
Measured value：450.1050(M+H)
Embodiment 214：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- (propyl- 1- alkene -2- bases) thieno [2,3-
D] pyrimidine-4-yl]-D-phenylalanine
With
Embodiment 215：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- (propyl- 1- alkene -2- bases) thieno [2,3-
D] pyrimidine-4-yl]-D-phenylalanine
Using universal method IIc, 5a is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine, 2- isopropenyl -4,
4,5,5- tetramethyls -1,3,2- dioxaborolanes obtain the mixing of diastereoisomer as appropriate boronic acid derivatives
Thing.They are by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Obtain embodiment
214, for the diastereoisomer more early eluted.HRMS C25H22ClN3O2S calculated values：463.1121, measured value：464.1178
(M+H)
Obtain embodiment 215, the diastereoisomer eluted after being.HRMS C25H22ClN3O2S calculated values：463.1121
Measured value：464.1179(M+H)
Embodiment 216：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- cyclopropyl-thieno [2,3-d] pyrimidine -
4- yls]-D-phenylalanine
With
Embodiment 217：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- cyclopropyl-thieno [2,3-d] pyrimidine -
4- yls]-D-phenylalanine
Using universal method IIa, 5a is prepared as the appropriate iodo- thienos of 6- [2,3-d] pyrimidine, cyclopropylboronic acid conduct
Appropriate boronic acid derivatives, Bu4NOH replaces K2CO3, obtain the mixture of diastereoisomer.They pass through the anti-phase color of preparative
Spectrum separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 216 is obtained, is different compared with the diastereomeric early eluted
Structure body.HRMS C25H22ClN3O2S calculated values：463.1121, measured value：464.1177(M+H)
Obtain embodiment 217, the diastereoisomer eluted after being.HRMS C25H22ClN3O2S calculated values：463.1121
Measured value：464.1182(M+H)
Embodiment 218：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- (propyl- 2- yls) thieno [2,3-d] is phonetic
Pyridine -4- bases]-L-phenylalanine
With
Embodiment 219：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- (propyl- 2- yls) thieno [2,3-d] is phonetic
Pyridine -4- bases]-L-phenylalanine
Using universal method Ib, 4u is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, L- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 218 is obtained, for the diastereoisomer more early eluted.
HRMS C25H24ClN3O2S calculated values：465.1278, measured value：466.1371(M+H)
Obtain embodiment 219, the diastereoisomer eluted after being.HRMS C25H24ClN3O2S calculated values：465.1278
Measured value：466.1361(M+H)
Embodiment 220：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- (propyl- 2- yls) thieno [2,3-d] is phonetic
Pyridine -4- bases]-D-phenylalanine
With
Embodiment 221：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- (propyl- 2- yls) thieno [2,3-d] is phonetic
Pyridine -4- bases]-D-phenylalanine
Using universal method Ib, 4u is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, D- phenylpropyl alcohols
Propylhomoserin obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through preparative reverse-phase chromatography point
From using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 220 is obtained, for the diastereoisomer more early eluted.
HRMS C25H24ClN3O2S calculated values：465.1278, measured value：466.1348(M+H)
Obtain embodiment 221, the diastereoisomer eluted after being.HRMS C25H24ClN3O2S calculated values：465.1278
Measured value：466.1350(M+H)
Embodiment 222：N-[(5Ra) -5- (3- chloro -2- aminomethyl phenyls) -6- (propyl- 2- yls) thieno [2,3-d] is phonetic
Pyridine -4- bases] -2- methoxyl groups-D-phenylalanine
With
Embodiment 223：N-[(5Sa) -5- (3- chloro -2- aminomethyl phenyls) -6- (propyl- 2- yls) thieno [2,3-d] is phonetic
Pyridine -4- bases] -2- methoxyl groups-D-phenylalanine
Using universal method Ib, 4u is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- methoxyphenyls) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They
By preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Obtain embodiment 222, be compared with
The diastereoisomer early eluted.HRMS C26H26ClN3O3S calculated values：495.1383, measured value：496.1460(M+H)
Obtain embodiment 223, the diastereoisomer eluted after being.HRMS C26H26ClN3O3S calculated values：495.1383
Measured value：496.1454(M+H)
Embodiment 224：N-[(5Ra) -5- (3- chloro -1H- indoles -4- bases) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine -
4- yls]-D-phenylalanine
With
Embodiment 225：N-[(5Sa) -5- (3- chloro -1H- indoles -4- bases) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine -
4- yls]-D-phenylalanine
522mg is prepared into 7h (1mMol), 164mg NCS (1.2mMol), 15mL CCl4With 10mL THF nitrogen at room temperature
Stirred 2 hours in compression ring border.Then pour the mixture into frozen water, extracted with DCM.The organic phase of merging is dried over sodium sulfate,
Filtering, filtrate decompression is concentrated.The diastereoisomer of formation is by preparative reversed phase chromatography separation, using 40mM NH4OAc
The aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Obtain embodiment 224, the diastereo-isomerism eluted after being
Body.HRMS C25H21ClN4O2S calculated values：476.1074, measured value：477.1133(M+H)
Embodiment 225 is obtained, for the diastereoisomer more early eluted.HRMS C25H21ClN4O2S calculated values：
476.1074, measured value：477.1137(M+H)
Embodiment 226：N-[(5Sa) -5- (the bromo- 1H- indoles -4- bases of 3-) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
With
Embodiment 227：N-[(5Ra) -5- (the bromo- 1H- indoles -4- bases of 3-) -6- ethylthiophenes simultaneously [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
522mg is prepared into 7h (1mMol), 216mg NBS (1.2mMol), 15mL CCl4With 5mL THF nitrogen at room temperature
Stirred 2 hours in compression ring border.Then pour the mixture into frozen water, extracted with DCM.The organic phase of merging is dried over sodium sulfate,
Filtering, filtrate decompression is concentrated.The diastereoisomer of formation is by preparative reversed phase chromatography separation, using 40mM NH4OAc
The aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.Embodiment 226 is obtained, is different compared with the diastereomeric early eluted
Structure body.HRMS C25H21BrN4O2S calculated values：520.0569, measured value：521.0653(M+H)
Obtain embodiment 227, the diastereoisomer eluted after being.HRMS C25H21BrN4O2S calculated values：520.0569
Measured value：521.0629(M+H)
Embodiment 228：N- [6- ethyls-(5Sa) -5- (the iodo- 1H- indoles -4- bases of 3-) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
With
Embodiment 229：N- [6- ethyls-(5Ra) -5- (the iodo- 1H- indoles -4- bases of 3-) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine
By 522mg prepare 7h (1mMol), 196mg KOH (3.5mMol), 15mL DMF and 267mg iodine (1.05mMol) in
Stirred 18 hours in nitrogen environment at room temperature.Then pour the mixture into frozen water, add the Na of saturation2S2O3Solution.Will mixing
Thing is extracted with DCM, and the organic phase of merging is dried over sodium sulfate, filtering, filtrate decompression is concentrated.The diastereoisomer of formation leads to
Preparative reversed phase chromatography separation is crossed, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as elution
Liquid.Embodiment 228 is obtained, for the diastereoisomer more early eluted.HRMS C25H21IN4O2S calculated values：568.043, actual measurement
Value：569.0498(M+H)
Obtain embodiment 229, the diastereoisomer eluted after being.HRMS C25H21IN4O2S calculated values：568.043, it is real
Measured value：569.0502(M+H)
Embodiment 230：N-((5Sa) -5- { 3- chloros -1- [2- (dimethylamino) ethyl] -1H- indoles -4- bases } -6-
Ethyl-thiophen simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
With
Embodiment 231：N-((5Ra) -5- { 3- chloros -1- [2- (dimethylamino) ethyl] -1H- indoles -4- bases } -6-
Ethyl-thiophen simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VIII, prepare 7i and make as appropriate indole derivatives, 2- (N, N- dimethylamino) ethanol
For appropriate alcohol, embodiment 230 is obtained, for the diastereoisomer more early eluted.HRMS C29H30ClN5O2S calculated values：
547.1809, measured value：548.1902(M+H)
Obtain embodiment 231, the diastereoisomer eluted after being.HRMS C29H30ClN5O2S calculated values：547.1809
Measured value：548.1889(M+H)
Embodiment 232：N-((5Ra) -5- { 3- chloros -1- [2- (pyrrolidin-1-yl) ethyl] -1H- indoles -4- bases } -6-
Ethyl-thiophen simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
With
Embodiment 233：N-((5Sa) -5- { 3- chloros -1- [2- (pyrrolidin-1-yl) ethyl] -1H- indoles -4- bases } -6-
Ethyl-thiophen simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VIII, 7i is prepared as appropriate indole derivatives, 2- pyrrolidin-1-yls ethanol is as appropriate
Alcohol, obtain embodiment 232, the diastereoisomer eluted after being.HRMS C31H32ClN5O2S calculated values：573.1965, it is real
Measured value：574.2059(M+H)
Embodiment 233 is obtained, for the diastereoisomer more early eluted.HRMS C31H32ClN5O2S calculated values：
573.1965, measured value：574.2060(M+H)
Embodiment 234：N-((5Ra) -5- { 3- chloros -1- [2- (piperidin-1-yl) ethyl] -1H- indoles -4- bases } -6- second
Base-thieno [2,3-d] pyrimidine-4-yl)-D-phenylalanine
With
Embodiment 235：N-((5Sa) -5- { 3- chloros -1- [2- (piperidin-1-yl) ethyl] -1H- indoles -4- bases } -6- second
Base-thieno [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VIII, 7i is prepared as appropriate indole derivatives, 2- (1- piperidyls) ethanol is as appropriate
Alcohol, obtain the mixture of diastereoisomer.They by preparative reversed phase chromatography separation, using the 0.1%TFA aqueous solution and
Acetonitrile is as eluent.Embodiment 234 is obtained, for the diastereoisomer more early eluted.HRMS C32H34ClN5O2S calculated values：
587.2122, measured value：588.2201(M+H)
Obtain embodiment 235, the diastereoisomer eluted after being.HRMS C32H34ClN5O2S calculated values：587.2122
Measured value：588.2199(M+H)
Embodiment 236：N-((5Ra) -5- { 3- chloros -1- [2- (morpholine -4- bases) ethyl] -1H- indoles -4- bases } -6- second
Base-thieno [2,3-d] pyrimidine-4-yl)-D-phenylalanine
With
Embodiment 237：N-((5Sa) -5- { 3- chloros -1- [2- (morpholine -4- bases) ethyl] -1H- indoles -4- bases } -6- second
Base-thieno [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VIII, prepare 7i as appropriate indole derivatives, 2- morpholinoes ethanol as appropriate alcohol,
Obtain embodiment 236, the diastereoisomer eluted after being.HRMS C31H32ClN5O3S calculated values：589.1914, measured value：
590.1998(M+H)
Embodiment 237 is obtained, for the diastereoisomer more early eluted.HRMS C31H32ClN5O3S calculated values：
589.1914, measured value：590.1994(M+H).
Embodiment 238：N-((5Sa) -5- { 3- chloros -1- [2- (4- methylpiperazine-1-yls) ethyl] -1H- indoles -4-
Base } -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
With
Embodiment 239：N-((5Ra) -5- { 3- chloros -1- [2- (4- methylpiperazine-1-yls) ethyl] -1H- indoles -4-
Base } -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VIII, prepare 7i and make as appropriate indole derivatives, 2- (4- methylpiperazine-1-yls) ethanol
For appropriate alcohol, embodiment 238 is obtained, for the diastereoisomer more early eluted.HRMS C32H35ClN6O2S calculated values：
602.2231, measured value：603.2312(M+H)
Obtain embodiment 239, the diastereoisomer eluted after being.HRMS C32H35ClN6O2S calculated values：602.2231
Measured value：603.2311(M+H)
Embodiment 240：N-((5Sa) -5- { 3- chloros -1- [3- (4- methylpiperazine-1-yls) propyl group] -1H- indoles -4-
Base } -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
With
Embodiment 241：N-((5Ra) -5- { 3- chloros -1- [3- (4- methylpiperazine-1-yls) propyl group] -1H- indoles -4-
Base } -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl)-D-phenylalanine
Using universal method VIII, 7i is prepared as appropriate indole derivatives, 3- (4- methylpiperazine-1-yls) propyl- 1-
Alcohol obtains embodiment 240, for the diastereoisomer more early eluted as appropriate alcohol.HRMS C33H37ClN6O2S calculated values：
616.2387, measured value：617.2466(M+H)
Obtain embodiment 241, the diastereoisomer eluted after being.HRMS C33H37ClN6O2S calculated values：616.2387
Measured value：617.2473(M+H)
Embodiment 242：3- cyclohexyl-N- [6- ethyls -5- (1H- indoles -4- bases) thieno [2,3-d] pyrimidine-4-yl] -
D-alanine, diastereoisomer 1
With
Embodiment 243：3- cyclohexyl-N- [6- ethyls -5- (1H- indoles -4- bases) thieno [2,3-d] pyrimidine-4-yl] -
D-alanine, diastereoisomer 2
Using universal method Ia, 4v is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- cyclohexyl-propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through system
Standby property reversed phase chromatography separation, using the 0.1%TFA aqueous solution and acetonitrile as eluent.Embodiment 242 is obtained, for relatively early elution
Diastereoisomer.HRMS C25H28N4O2S calculated values：448.1933, measured value：449.1994(M+H)
Obtain embodiment 243, the diastereoisomer eluted after being.HRMS C25H28N4O2S calculated values：448.1933, it is real
Measured value：449.2006(M+H)
Embodiment 244：N-[(5Sa) -5- (3- chloro -1H- indoles -4- bases) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine -
4- yls] -3- pyridines -2- bases-D-alanine
With
Embodiment 245：N-[(5Ra) -5- (3- chloro -1H- indoles -4- bases) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine -
4- yls] -3- pyridines -2- bases-D-alanine
Using universal method Ia, 7j is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- pyridine radicals) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through
Preparative reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.
Embodiment 244 is obtained, for the diastereoisomer more early eluted.HRMS C24H20ClN5O2S calculated values：477.1026, actual measurement
Value：478.1087(M+H)
Obtain embodiment 245, the diastereoisomer eluted after being.HRMS C24H20ClN5O2S calculated values：477.1026
Measured value：478.1089(M+H)
Embodiment 246：N-((5Sa) -5- { 3- chloros -1- [2- (morpholine -4- bases) ethyl] -1H- indoles -4- bases } -6- second
Base-thieno [2,3-d] pyrimidine-4-yl) -3- pyridines -2- bases-D-alanine
Step A：(2R)-2-[[(5Sa) simultaneously [2,3-d] is phonetic for -6- ethyl-thiophens by -5- (3- chloro -1H- indoles -4- bases)
Pyridine -4- bases] amino] -3- (2- pyridine radicals) methyl propionate
0.13g embodiments 244 (0.27mMol) are dissolved in 13mL MeOH, then add 0.3mL cc.H2SO4, will mix
Thing stirs until further conversion is not observed at room temperature.Then it is concentrated under reduced pressure, adds the NaHCO of saturation3Water
Solution, shake mixture.The sediment to be formed is collected by filtration, obtains (2R) -2- [[(5Sa) -5- (3- chloro -1H- indoles -4-
Base) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl] amino] -3- (2- pyridine radicals) methyl propionate.
Step B：Embodiment 246
Using universal method VIII, (2R) -2- [[(5Sa) -6- ethyl-thiophens are simultaneously by -5- (3- chloro -1H- indoles -4- bases)
[2,3-d] pyrimidine-4-yl] amino] -3- (2- pyridine radicals) methyl propionates are as appropriate indole derivatives, 2- morpholino ethanol
As appropriate alcohol, embodiment 246 is obtained.HRMS C30H31ClN6O3S calculated values：590.1867, measured value：591.1938(M+
H)
Embodiment 247：N-((5Ra) -5- { 3- chloros -1- [2- (morpholine -4- bases) ethyl] -1H- indoles -4- bases } -6- second
Base-thieno [2,3-d] pyrimidine-4-yl) -3- pyridines -2- bases-D-alanine
Step A：(2R)-2-[[(5Ra) simultaneously [2,3-d] is phonetic for -6- ethyl-thiophens by -5- (3- chloro -1H- indoles -4- bases)
Pyridine -4- bases] amino] -3- (2- pyridine radicals) methyl propionate
0.157g embodiments 245 (0.33mMol) are dissolved in 15mL MeOH, then add 0.3mL cc.H2SO4, will mix
Thing stirs until further conversion is not observed at room temperature.Then it is concentrated under reduced pressure, adds the NaHCO of saturation3Water
Solution, shake mixture.The sediment to be formed is collected by filtration, obtains (2R) -2- [[(5Ra) -5- (3- chloro -1H- indoles -4-
Base) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl] amino] -3- (2- pyridine radicals) methyl propionate.
Step B：Embodiment 247
Using universal method VIII, (2R) -2- [[(5Ra) -6- ethyl-thiophens are simultaneously by -5- (3- chloro -1H- indoles -4- bases)
[2,3-d] pyrimidine-4-yl] amino] -3- (2- pyridine radicals) methyl propionates are as appropriate amine, and 2- morpholinoes ethanol is as appropriate
Alcohol, obtain embodiment 247.HRMS C30H31ClN6O3S calculated values：590.1867, measured value：591.1918(M+H)
Embodiment 248：N-((5Sa) -5- { 3- chloros -1- [2- (4- methylpiperazine-1-yls) ethyl] -1H- indoles -4-
Base } -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl) -3- pyridines -2- bases-D-alanine
Step A：(2R)-2-[[(5Sa) simultaneously [2,3-d] is phonetic for -6- ethyl-thiophens by -5- (3- chloro -1H- indoles -4- bases)
Pyridine -4- bases] amino] -3- (2- pyridine radicals) methyl propionate
0.13g embodiments 244 (0.27mMol) are dissolved in 13mL MeOH, then add 0.3mL cc.H2SO4, will mix
Thing stirs until further conversion is not observed at room temperature.Then it is concentrated under reduced pressure, adds the NaHCO of saturation3Water
Solution, shake mixture.The sediment to be formed is collected by filtration, obtains (2R) -2- [[(5Sa) -5- (3- chloro -1H- indoles -4-
Base) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl] amino] -3- (2- pyridine radicals) methyl propionate.
Step B：Embodiment 248
Using universal method VIII, (2R) -2- [[(5Sa) -6- ethyl-thiophens are simultaneously by -5- (3- chloro -1H- indoles -4- bases)
[2,3-d] pyrimidine-4-yl] amino] -3- (2- pyridine radicals) methyl propionates are as appropriate indole derivatives, 2- (4- methyl piperazines
Piperazine -1- bases) ethanol as appropriate alcohol, obtains embodiment 248.HRMSC31H34ClN7O2S calculated values：603.2183, measured value：
302.6172(M+2H)
Embodiment 249：N-((5Ra) -5- { 3- chloros -1- [2- (4- methylpiperazine-1-yls) ethyl] -1H- indoles -4-
Base } -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl) -3- pyridines -2- bases-D-alanine
Step A：(2R)-2-[[(5Ra) simultaneously [2,3-d] is phonetic for -6- ethyl-thiophens by -5- (3- chloro -1H- indoles -4- bases)
Pyridine -4- bases] amino] -3- (2- pyridine radicals) methyl propionate
0.157g embodiments 245 (0.33mMol) are dissolved in 15mL MeOH, then add 0.3mL cc.H2SO4, will mix
Thing stirs until further conversion is not observed at room temperature.Then it is concentrated under reduced pressure, adds the NaHCO of saturation3Water
Solution, shake mixture.The sediment to be formed is collected by filtration, obtains (2R) -2- [[(5Ra) -5- (3- chloro -1H- indoles -4-
Base) -6- ethyl-thiophens simultaneously [2,3-d] pyrimidine-4-yl] amino] -3- (2- pyridine radicals) methyl propionate.
Step B：Embodiment 249
Using universal method VIII, (2R) -2- [[(5Ra) -6- ethylthiophenes are simultaneously by -5- (3- chloro -1H- indoles -4- bases)
[2,3-d] pyrimidine-4-yl] amino] -3- (2- pyridine radicals) methyl propionates are as appropriate indole derivatives, 2- (4- methyl piperazines
Piperazine -1- bases) ethanol as appropriate alcohol, obtains embodiment 249.HRMS C31H34ClN7O2S calculated values：603.2183, actual measurement
Value：302.6164(M+2H)
Embodiment 250：N- [6- (difluoromethyl)-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -3-
Pyridine -2- bases-D-alanine
With
Embodiment 251：N- [6- (difluoromethyl)-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl] -3-
Pyridine -2- bases-D-alanine
Using universal method Ia, 4r is prepared as appropriate 4- chloros-thieno [2,3-d] pyrimidine derivatives, (2R) -2-
Amino -3- (2- pyridine radicals) propionic acid obtains the mixture of diastereoisomer as appropriate amino acid derivativges.They pass through
Preparative reversed phase chromatography separation, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are as eluent.
Embodiment 250 is obtained, for the diastereoisomer more early eluted.HRMS C25H18F2N4O2S calculated values：476.1119, actual measurement
Value：477.1195(M+H)
Obtain embodiment 251, the diastereoisomer eluted after being.HRMS C25H18F2N4O2S calculated values：476.1119
Measured value：477.1182(M+H)
Embodiment 252：N-[(5Sa) -5- (naphthalene -1- bases) -6- propyl group thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid
266mg embodiments 108 (0.57mMol) are dissolved in 10mL MeOH and 2mL AcOH, then add 61mg 10%
Pd/C.Mixture is stirred 2 hours in 40 DEG C of hydrogen environments.It is filtered by diatomite, filtrate decompression is concentrated.Crude product
Product is by preparative Reverse phase chromatography, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are made
For eluent, embodiment 252 is obtained.HRMS C28H25N3O2S calculated values：467.1667, measured value：468.1746(M+H)
Embodiment 253：N-[(5Ra) -5- (naphthalene -1- bases) -6- propyl group thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Acid
266mg embodiments 109 (0.57mMol) are dissolved in 10mL MeOH and 2mL AcOH, then add 61mg 10%
Pd/C.Mixture is stirred 2 hours in 40 DEG C of hydrogen environments.It is filtered by diatomite, filtrate decompression is concentrated.Crude product
Product is by preparative Reverse phase chromatography, using 40mM NH4The OAc aqueous solution (pH=4, being adjusted using AcOH) and acetonitrile are made
For eluent, embodiment 253 is obtained.HRMS C28H25N3O2S calculated values：467.1667, measured value：468.1736(M+H)
Embodiment 254：N- [6- ethyls-(5Sa) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Sour methyl esters
102mg embodiments 101 (0.225mMol) are dissolved in 2mL MeOH, mixture is cooled to 0 in nitrogen environment
℃.Then 135 μ L dizaomethyls (trimethyl) solution of silane (2M Et are added2O solution), mixture is warmed to room temperature.So
Mixture is concentrated in vacuo afterwards, by purification by flash chromatography, using heptane and EtOAc as eluent, obtains embodiment 254.
HRMS C28H25N3O2S calculated values：467.1667, measured value：468.1746(M+H)
Embodiment 255：N- [6- ethyls-(5Ra) -5- (naphthalene -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D- phenylpropyl alcohol ammonia
Sour methyl esters
102mg embodiments 100 (0.225mMol) are dissolved in 2mL MeOH, mixture is cooled to 0 in nitrogen environment
℃.Then 135 μ L dizaomethyls (trimethyl) solution of silane (2M Et are added2O solution), mixture is warmed to room temperature.Will
Mixture is concentrated in vacuo, and by purification by flash chromatography, using heptane and EtOAc as eluent, obtains embodiment 255.HRMS
C28H25N3O2S calculated values：467.1667, measured value：468.1737(M+H)
Embodiment 256：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxies
Base }-D-phenylalanine ethyl ester
Embodiment 7 is dissolved in HCl solution (20mL/mmol, 1.25M EtOH solution), mixture is stirred at room temperature
Is then by mixture NaHCO overnight3Solution is neutralized, and it is extracted with DCM.Organic phase is dried over sodium sulfate, filtering, will filter
Liquid is concentrated under reduced pressure.Crude material is by preparative Reverse phase chromatography, using 25mM NH4HCO3The aqueous solution and acetonitrile are as elution
Liquid, obtain embodiment 256.HRMS C49H49ClFN7O5S calculated values：901.3188, measured value：902.3225(M+H)
Embodiment 257：2- [(1- tert-butyl -1H- pyrazoles -5- bases) methoxyl group]-N- [(5Sa) -5- { 3- chloro -2- first
Base -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine -4-
Base]-D-phenylalanine ethyl ester
Embodiment 40 is dissolved in HCl solution (20mL/mmol, 1.25M EtOH solution), mixture is stirred at room temperature
Is then by mixture NaHCO overnight3Solution is neutralized, and it is extracted with DCM.Organic phase is dried over sodium sulfate, filtering, will filter
Liquid is concentrated under reduced pressure.Crude material is by preparative Reverse phase chromatography, using 25mM NH4HCO3The aqueous solution and acetonitrile are as elution
Liquid, obtain embodiment 257.HRMS C42H50ClN7O4S calculated values：783.3334, measured value：392.6744(M+2H)
Embodiment 258：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] first
Epoxide }-D-phenylalanine ethyl ester
Embodiment 45 is dissolved in HCl solution (20mL/mmol, 1.25M EtOH solution), mixture is stirred at room temperature
Is then by mixture NaHCO overnight3Solution is neutralized, and it is extracted with DCM.Organic phase is dried over sodium sulfate, filtering, will filter
Liquid is concentrated under reduced pressure.Crude material is by preparative Reverse phase chromatography, using 25mM NH4HCO3The aqueous solution and acetonitrile are as elution
Liquid, obtain embodiment 258.HRMS C46H48ClN7O5S calculated values：845.3126, measured value：423.6650(M+H)
Embodiment 259：N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6-
(propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group } -
D-phenylalanine ethyl ester
Embodiment 49 is dissolved in HCl solution (20mL/mmol, 1.25M EtOH solution), mixture is stirred at room temperature
Overnight.Then by mixture NaHCO3Solution is neutralized, and it is extracted with DCM.Organic phase is dried over sodium sulfate, filtering, will filter
Liquid is concentrated under reduced pressure.Crude material is by preparative Reverse phase chromatography, using 25mM NH4HCO3The aqueous solution and acetonitrile are as elution
Liquid, obtain embodiment 259.HRMS C43H43ClN6O5S calculated values：790.2704, measured value：396.1425(M+2H)
Embodiment 260：N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6-
(4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- ({ 2- [2- (2- methoxy ethoxies) phenyl] pyrimidine-4-yl } first
Epoxide)-D-phenylalanine ethyl ester
Embodiment 51 is dissolved in HCl solution (20mL/mmol, 1.25M EtOH solution), mixture is straight in 60 DEG C of stirrings
To further conversion is not observed.Then by mixture NaHCO3Solution is neutralized, and it is extracted with DCM.Organic phase passes through
Sodium sulphate is dried, and filtering, filtrate decompression is concentrated.Crude material is by preparative Reverse phase chromatography, using 25mM NH4HCO3
The aqueous solution and acetonitrile obtain embodiment 260 as eluent.HRMS C48H48ClFN6O6S calculated values：890.3029, measured value：
891.3105(M+H)
Embodiment 261：(5- methyl -2- oxo -1,3- dioxole -4- bases) methyl N-[(5Sa) -5- { 3- chlorine
Generation -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -
2- ({ 2- [2- (2- methoxy ethoxies) phenyl] pyrimidine-4-yl } methoxyl group)-D-phenylalanine ester
By 1eq. embodiments 51 and 1.1eq.4- (chloromethyl) -5- methyl isophthalic acids, 3- dioxole -2- ketone is dissolved in
DMF (10mL/mmol), then add 2eq.NaI and 2eq.Cs2CO3, stir the mixture for further until being not observed
Conversion.Then by mixture direct injection, by preparative Reverse phase chromatography, using 25mM NH4HCO3The aqueous solution and acetonitrile
As eluent, embodiment 261 is obtained.HRMS C51H48ClFN6O9S calculated values：974.2876, measured value：975.2949(M+
H)
Embodiment 262:N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxies
Base }-D-phenylalanine 1- [(ethoxy carbonyl) epoxide] ethyl ester
Embodiment 263:N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxies
Base }-D-phenylalanine 1- [(formyl-dimethylamino) epoxide] ethyl ester
Embodiment 264：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- ({ 2- [3- (hydroxymethyl) phenyl] pyrimidine-4-yl } first
Epoxide)-D-phenylalanine
Embodiment 265：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- ({ 2- [2- (hydroxymethyl) pyridin-4-yl] pyrimidine -4-
Base } methoxyl group)-D-phenylalanine
Embodiment 266：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- ({ 2- [6- (hydroxymethyl) pyridazine -4- bases] pyrimidine -4-
Base } methoxyl group)-D-phenylalanine
Embodiment 267：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- ({ 2- [6- (hydroxymethyl) pyrazine -2- bases] pyrimidine -4-
Base } methoxyl group)-D-phenylalanine
Embodiment 268：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2'- (hydroxymethyl) -2,5'- joins pyrimidine-4-yl] first
Epoxide }-D-phenylalanine
Embodiment 269：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- ({ 2- [4- (phosphinylidyne epoxide) phenyl] pyrimidine-4-yl } first
Epoxide)-D-phenylalanine
Embodiment 270：N- [5- { 3,5- dichloro- -2,6- dimethyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxies
Base }-D-phenylalanine
Step A：The bromo- 2,6- dichloro-s -3,5- dimethyl-phenol of 4-
The bromo- 3,5- dimethyl of 30.16g 4--phenol (150mMol) is dissolved in 75mL 1,2- dichloroethanes and 75mL acetonitriles
Mixture in, then by several times add 40.06g NCS (300mMol), mixture is stirred until being not observed at room temperature
Further conversion.Reactant mixture is concentrated under reduced pressure, dissolves the residue in DCM, with water and salt water washing.Organic layer is through sulfuric acid
Sodium is dried, and is concentrated under reduced pressure, it need not be further purified and be used directly for next step.1H NMR(400MHz,DMSO-d6):
10.10(s,1H),2.46(s,6H)
Step B:The bromo- 3,5- dichloro-s -4- methoxyl groups -2,6- dimethyl-benzene of 1-
To the bromo- 2,6- dichloro-s -3,5- dimethyl of 26.0g 4--phenol (96.3mMol) and 26.6g K2CO3
6.6mL MeI (105.9mMol) are added in the 300mL MeCN solution of (192.6mMol), mixture are stirred at room temperature straight
To further conversion is not observed.Filter solid is crossed, filtrate decompression is concentrated.Crude material is dissolved in DCM, is washed with water and salt
Wash.Organic layer is dried over sodium sulfate, is concentrated under reduced pressure, and it need not be further purified and be used directly for next step.1H NMR
(400MHz,DMSO-d6)：3.78(s,3H),2.49(s,6H)
Step C：2- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -4,4,5,5- tetramethyls -1,3,2- two
Oxa- ring pentaborane
By the bromo- 3,5- dichloro-s -4- methoxyl groups -2,6- dimethyl of 10.0g 1--benzene (35.2mMol) in nitrogen environment
The anhydrous THF of 360mL are dissolved in, -78 DEG C are cooled to dry ice-propanone.Add 23.2mL nBuLi (1.6M hexane solution)
(37.0mMol), stir the mixture for 15 minutes, then add 8.6mL 2- isopropoxies -4,4,5,5- tetramethyls -1,3,2-
Dioxaborolanes (42.24mMol), mixture is warmed to room temperature.It is quenched with salt solution, extracted with DCM, through sulfuric acid
Sodium is dried, and filtering, is concentrated under reduced pressure.Crude material, using heptane and EtOAc as eluent, is obtained by purification by flash chromatography
2- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -4,4,5,5- tetramethyl -1,3,2- dioxaborolanes.1H NMR(400MHz,DMSO-d6)：3.81(s,3H),2.33(s,6H),1.34(s,12H)
Step D：4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) thiophene -3- Ethyl formates
By 3.92g 4- bromothiophene -3- Ethyl formates (16.68mMol) and 9.9g 2- (3,5- dichloro- -4- methoxyl groups -
2,6- Dimethvl-phenyls) -4,4,5,5- tetramethyl -1,3,2- dioxaborolanes (30.0mMol) are dissolved in 140mL dioxies six
Ring, then add the 10.87g Cs for being dissolved in 40mL water2CO3(33.36mMol).Then add 590mg AtaPhos
(0.83mMol), by mixture in nitrogen environment in stirred under reflux temperature until further conversion is not observed.So
It is diluted with DCM and salt solution afterwards, after phase separation, aqueous phase is extracted with DCM.Merge organic layer, it is dried over sodium sulfate, filtering, subtract
Pressure concentration.Crude material is by purification by flash chromatography, using heptane and EtOAc as eluent, obtain 4- (3,5- dichloro-s-
4- methoxyl group -2,6- Dimethvl-phenyls) thiophene -3- Ethyl formates.
1H NMR(400MHz,DMSO-d6)：8.53(d,1H),7.47(d,1H),4.02(q,2H),3.83(s,3H),
1.95(s,6H),1.00(t,3H)
HRMS(M+NH4)+=376.0538
Step E：4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) iodo- thiophene -3- formic acid second of -2,5- two
Ester
By 2.65g 4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) thiophene -3- formic acid esters
(7.38mMol) is dissolved in 75mL acetonitriles, then adds 2.2mL fluoboric acid ether complex (16.23mMol) and 3.65g N- iodine ambers
Amber acid imide (16.23mMol), mixture is stirred until further conversion is not observed at room temperature.Reaction is mixed
Thing is concentrated under reduced pressure, and crude material, using heptane and EtOAc as eluent, obtains 4- (3,5- dichloros by purification by flash chromatography
Generation -4- methoxyl group -2,6- Dimethvl-phenyls) the iodo- thiophene -3- Ethyl formates of -2,5- two.1H NMR(400MHz,DMSO-d6)：
3.98(q,2H),3.84(s,3H),1.92(s,6H),0.84(t,3H)
Step F：4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) iodo- thiophene -3- Ethyl formates of -5-
By 5.29g 4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) iodo- thiophene -3- formic acid of -2,5- two
Ester (8.66mMol) is dissolved in the anhydrous THF of 90mL, and -78 DEG C are then cooled in ar gas environment.Add 6.7mL isopropyl chlorinations
Magnesium, lithium chloride compound (1.3M THF solution) (8.66mMol), mixture is stirred 30 minutes in -78 DEG C.Then add full
The aq.NH of sum4Cl, mixture is extracted with ethyl acetate.Organic layer is dried over sodium sulfate and is concentrated under reduced pressure.Crude material passes through
Purification by flash chromatography, using heptane and EtOAc as eluent, obtain 4- (3,5- dichloro- -4- methoxyl groups -2,6- dimethyl -
Phenyl) the iodo- thiophene -3- Ethyl formates of -5-.1H NMR(400MHz,DMSO-d6)：8.71(s,1H),4.01(q,2H),3.86
(s,3H),1.89(s,6H),0.99(t,3H)
Step G：4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -5- (4- fluorophenyls) thiophene -3- formic acid
Ethyl ester
By 4.20g 4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) iodo- thiophene -3- Ethyl formates of -5-
(8.66mMol) and 1.82g 4- flurophenyl boronic acids (13.0mMol) are dissolved in 80mL dioxane, then add and are dissolved in 20mL water
5.64g Cs2CO3(17.32mMol).Then 500mg Pd (PPh are added3)4(0.43mMol), by mixture in nitrogen environment
In in 80 DEG C stirring until further conversion is not observed.Then it is diluted with DCM, salt water washing.After phase separation, water
Mutually extracted with DCM.Merge organic layer, it is dried over sodium sulfate, filtering, it is concentrated under reduced pressure.Crude material is adopted by purification by flash chromatography
By the use of heptane and EtOAc as eluent, 4- (3,5- dichloro- -4- methoxyl groups -2,6- Dimethvl-phenyl) -5- (4- fluorobenzene is obtained
Base) thiophene -3- Ethyl formates.
1H NMR(400MHz,DMSO-d6)：8.58(s,1H),7.22-7.10(m,4H),4.03(q,2H),3.82(s,
3H),1.92(s,6H),1.00(t,3H)
HRMS(M+H)+=453.0498
Step H：4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -5- (4- fluorophenyls) -2- nitros-thiophene
Fen -3- Ethyl formates
By 1.97g 4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -5- (4- fluorophenyls) thiophene -3- first
Acetoacetic ester (4.34mMol) is dissolved in 40mL anhydrous acetonitriles, then add 576mg nitronium tetrafluoroborates (4.34mMol), by mixture in
Stir at room temperature until further conversion is not observed.Then it is diluted with DCM, salt water washing.After phase separation, aqueous phase
Extracted with DCM.Merge organic layer, it is dried over sodium sulfate, filtering, it is concentrated under reduced pressure.Crude material is used by purification by flash chromatography
Heptane and EtOAc obtain 4- (3,5- dichloro- -4- methoxyl groups -2,6- Dimethvl-phenyl) -5- (4- fluorobenzene as eluent
Base) -2- Nitro-thiophene -3- Ethyl formates.1H NMR(400MHz,DMSO-d6)：7.37-7.33(m,2H),7.32-7.26(m,
2H),4.14(q,2H),3.82(s,3H),2.06(s,6H),0.88(t,3H)
Step I：2- amino -4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -5- (4- fluorophenyls) thiophene
Fen -3- Ethyl formates
By 1.85g 4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -5- (4- fluorophenyls) -2- nitros -
Thiophene -3- Ethyl formates (3.71mMol) are dissolved in the mixture of 90mL acetic acid and 18mL water, then add 2.43g zinc powders by several times
(37.1mMol), mixture is stirred until further conversion is not observed at room temperature.Reactant mixture is depressurized dense
Contracting, crude material, using heptane and EtOAc as eluent, obtain 2- amino -4- (3,5- dichloros by purification by flash chromatography
Generation -4- methoxyl group -2,6- Dimethvl-phenyls) -5- (4- fluorophenyls) thiophene -3- Ethyl formates.
1H NMR(400MHz,DMSO-d6)：7.73(s,2H),7.12-7.06(m,2H),7.02-6.97(m,2H),
3.86-3.80(m,2H),3.80(s,3H),2.01(s,6H),0.72(t,3H)
HRMS(M+H)+=456.0598
Step J：5- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -6- (4- fluorophenyls) -3H- thienos
[2,3-d] pyrimidin-4-one
By 1.1g 2- amino -4- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -5- (4- fluorophenyls) thiophene
Fen -3- Ethyl formates (2.35mMol) are dissolved in 20mL formamides, and it is further turned in 150 DEG C of stirrings until being not observed
Change.Then be poured into water, be collected by filtration the product of precipitation, obtain 5- (3,5- dichloro- -4- methoxyl groups -2,6- dimethyl -
Phenyl) -6- (4- fluorophenyls) -3H- thienos [2,3-d] pyrimidin-4-one.
1H NMR(400MHz,DMSO-d6):12.53(br s,1H),8.18(s,1H),7.23-7.16(m,4H),3.84
(s,3H),1.96(s,6H)
HRMS(M+H)+=449.0289
Step K：4- chloros -5- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -6- (4- fluorophenyls) thiophene
And [2,3-d] pyrimidine
By 700mg 5- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -6- (4- fluorophenyls) -3H- thiophene
It is and [2,3-d] pyrimidin-4-one (1.56mMol) is dissolved in 6mL phosphoryl chloride phosphorus oxychlorides, it is further until being not observed in 90 DEG C of stirrings
Conversion.Reactant mixture is concentrated under reduced pressure, frozen water is then added into crude material, it is ultrasonic 10 minutes.Pass through filtering
The product of precipitation is collected, obtains 4- chloros -5- (3,5- dichloro- -4- methoxyl groups -2,6- Dimethvl-phenyl) -6- (4- fluorobenzene
Base) thieno [2,3-d] pyrimidine
1H NMR(400MHz,DMSO-d6)：9.02(s,1H),7.38-7.26(m,4H),3.86(s,3H),1.99(s,
6H)
HRMS(M+H)+=466.9954
Step L：2,6- dichloro-s -4- [4- chloros -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine -5- bases] -3,5- two
Methyl-phenol and 4- [the bromo- 6- of 4- (4- fluorophenyls) thieno [2,3-d] pyrimidine -5- bases] -2,6- dichloro- -3,5- dimethyl -
Phenol
In 0 DEG C of 4- chloros -5- (3,5- dichloro- -4- methoxyl group -2,6- Dimethvl-phenyls) -6- from 700mg to stirring
Added in the 15mL DCM solution of (4- fluorophenyls) thieno [2,3-d] pyrimidine (1.50mMol) 3.0mL Boron tribromides (1M's
DCM solution) (3.0mMol), mixture is warmed to room temperature, is stirred for until further conversion is not observed.Will be mixed
The aq.NH of compound saturation4Cl is quenched, and is extracted with DCM.The organic phase of merging is dried over sodium sulfate and is concentrated under reduced pressure.Residue
By purification by flash chromatography, using heptane and EtOAc as eluent, 2,6- dichloro-s -4- [4- chloros -6- (4- fluorobenzene is obtained
Base) thieno [2,3-d] pyrimidine -5- bases] -3,5- dimethyl-phenol and 4- [the bromo- 6- of 4- (4- fluorophenyls) thienos [2,3-d]
Pyrimidine -5- bases] -2,6- dichloro-s -3,5- dimethyl-phenol is 37:63 product mixtures.
1H NMR(400MHz,DMSO-d6):10.14(br s,1H),9.01(s,1H),7.40-7.23(m,4H),1.95
(s, 6H) and 10.14 (br s, 1H), 8.93 (s, 1H), 7.40-7.23 (m, 4H), 1.93 (s, 6H)
HRMS(M+H)+=452.9800 and 496.9287
Step M：4- chloros -5- [3,5- dichloro- -2,6- dimethyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidines and the bromo- 5- of 4- [3,5- dichloro- -2,6- dimethyl -4- [2- (4- methyl
Piperazine -1- bases) ethyoxyl] phenyl] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine
By 300mg 2,6- dichloro-s -4- [4- chloros -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine -5- bases] -3,
5- dimethyl-phenol and 4- [the bromo- 6- of 4- (4- fluorophenyls) thieno [2,3-d] pyrimidine -5- bases] -2,6- dichloro-s -3,5- two
The mixture of methyl-phenol (0.62mMol), 286mg 2- (4- methylpiperazine-1-yls) ethanol (1.98mMol) and 520mg tri-
Phenylphosphine (1.98mMol) is dissolved in 10mL dry toluenes, then adds 460mg azoformic acid di-t-butyl esters (1.98mMol).
Mixture is stirred until further conversion is not observed in 50 DEG C of nitrogen environments.Volatiles evaporated in vacuo, in crude product
Mesosome, using EtOAc and methanol as eluent, obtains 4- chloros -5- [3,5- dichloro-s -2,6- by purification by flash chromatography
Dimethyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidines and 4-
Bromo- 5- [3,5- dichloro- -2,6- dimethyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6- (4- fluorophenyls) thiophene
Fen simultaneously [2,3-d] pyrimidine, it is 35:65 product mixtures.
1H NMR(400MHz,DMSO-d6)：9.02(S,1H),7.40-7.22(m,4H),4.11(t,2H),2.78(t,
2H), 2.63-2.20 (m, 8H), 2.17 (br s, 3H), 1.98 (s, 6H) and 8.94 (S, 1H), 7.40-7.22 (m, 4H), 4.11
(t,2H),2.78(t,2H),2.63-2.20(m,8H),2.15(br s,3H),1.98(s,6H)
HRMS(M+H)+=579.0968 and 623.0455
Step N：Embodiment 270
By 250mg 4- chloros -5- [3,5- dichloro- -2,6- dimethyl -4- [2- (4- methylpiperazine-1-yls) ethoxies
Base] phenyl] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidines and the bromo- 5- of 4- [3,5- dichloro- -2,6- dimethyl -4- [2-
(4- methylpiperazine-1-yls) ethyoxyl] phenyl] -6- (4- fluorophenyls) thieno [2,3-d] pyrimidines (0.41mMol) mixing
Thing, 327mg (2R) -2- amino -3- [2- [[2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group] phenyl] propionic acid (prepare A4,
0.86mMol) and 280mg Cs2CO3(0.86mMol) is dissolved in 5mL tert-butanols, by mixture in 70 DEG C of stirrings until not observing
To further conversion.Solid is filtered out, filtrate decompression is concentrated.Crude material is used by preparative Reverse phase chromatography
25mMNH4HCO3The aqueous solution and MeCN elutions, obtain embodiment 270.HRMS C48H46N7O5FSCl2Calculated value：921.2642, it is real
Measured value：461.6398(M+2H)
Embodiment 271：N- [5- { 2,6- dimethyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorine
Phenyl) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine
Embodiment 272：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] { [2- (2- methoxyphenyls) is phonetic by-β-(hydroxymethyl) -2-
Pyridine -4- bases] methoxyl group } phenylalanine
Embodiment 273：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl]-beta-hydroxy -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl]
Methoxyl group } phenylalanine
Embodiment 274：N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] benzene
Base } -6- (4- fluorophenyls) thieno [2,3-d] pyrimidine-4-yl] { [2- (2- methoxyphenyls) is phonetic by-β-(2- hydroxyethyls) -2-
Pyridine -4- bases] methoxyl group } phenylalanine
Pharmaceutical research
Embodiment A：Mcl-1 is suppressed by fluorescence polarization technology
The relative of every kind of compound is determined by fluorescence polarization (FP) and combines efficiency.This method use and Mcl-1 albumen knots
Fluorescein-labeled part (fluorescein-β the Ala-Ahx-A-REIGAQLRRMADDLNAQY-OH closed；Mw 2,765) (so that
Mcl-1 corresponds toEnter to hide registration number (primary accession number)：Q07820), so as to leading
Cause to use reader to polarize the anisotropy increase of (milli-polarisation) (mP) unit measurement in the least.Competitive binding
Addition with the compound of part same loci causes the ratio of unbound ligand in system to increase, by the reduction table of mP units
Show.
Method 1：11 serial dilutions of various compounds are prepared in DMSO, 2 μ l are transferred to flat low combination
In 384 orifice plates (final DMSO concentration 5%).Then add and contain fluorescein-labeled part (final concentration 1nM) and Mcl-1 albumen
Matter (final concentration 5nM) 38 μ l buffer solutions (10mM 4- (2- ethoxys) -1- piperazine ethanesulfonic acids [HEPES], 150mM NaCl,
0.05% polysorbas20, pH7.4).
FP is being measured with Biomek Synergy2 readout instruments (Ex.528nm, Em.640nm, ending 510nm) and calculates mP
Before unit, breadboard is incubated at room temperature about 2 hours.The combination of the test compound of ascending-dose is expressed as and " only
There is the window established between 5%DMSO " and " 100% suppresses " control to compare the percentage that mP is reduced.Using 4- parameter logistic moulds
Type (S-shaped dosage-response model), 11 dose point response curves are drawn with XL-Fit softwares, determining the mP provided reduces
50% inhibition concentration (IC50).Using method 1 obtain result as shown in Table 1 below；The IC that Mcl-1 suppresses50Not lower stroke
Line.
Method 2：11 serial dilutions of various compounds are prepared in DMSO, 2 μ l are transferred to flat low combination
In 384 orifice plates (final DMSO concentration 5%).Then add and contain fluorescein-labeled part (final concentration 10nM) and Mcl-1 eggs
38 μ l buffer solutions (20mM Na of white matter (final concentration 10nM)2HPO4,1mM EDTA,50mM NaCl,pH 7.4)。
FP is being measured with Biomek Synergy2 readout instruments (Ex.528nm, Em.640nm, ending 510nm) and calculates mP
Before unit, breadboard is incubated at room temperature about 2 hours.The combination of the test compound of ascending-dose is expressed as and " only
There is the window established between 5%DMSO " and " 100% suppresses " control (50 μM of unmarked parts) to compare the percentage that mP is reduced.
Using 4- parameter logistic models (S-shaped dosage-response model), 11 dose point response curves are drawn with XL-Fit softwares,
Determining the mP provided reduces by 50% inhibition concentration (IC50).Using method 2 obtain result as shown in Table 1 below；Using method
The IC that 2 Mcl-1 obtained suppress50There is underscore.
As a result show, the compounds of this invention can suppress the phase between Mcl-1 protein and the above fluorescent peptide
Interaction.
Embodiment B：Vitro cytotoxicity
Study of cytotoxicity is carried out in H929 huppert's disease tumour cell lines.
Cell is assigned on micro plate and is exposed to test compound 48 hours.Then it is thin by colorimetric estimation-micro
Born of the same parents cultivate tetrazolium and examine (Cancer Res., 1987,47,939-942) to quantitative determine cell viability.
As a result with IC50(concentration that can suppress the compound of 50% cell viability) represents, is listed in the table below in 1.
As a result showing the compound of the present invention has cytotoxicity.
Table 1：The IC that Mcl-1 suppresses50The IC of (fluorescence polarization assay) and cytotoxicity to H929 cells50
Pay attention to：The IC that the Mcl-1 obtained using method 2 is suppressed50There is underscore
ND：Undetermined
For partial inhibitor, the fluorescence polarization suppression percentage of the test compound of given concentration is indicated.Therefore,
45.1% 10 μM of@refers to observe that 45.1% fluorescence polarization suppresses for the concentration of 10 μM of test compound.
Embodiment C：The quantitative test of internal PARP cracking form
In the heteroplastic transplantation model of AMO-1 multiple myeloma cells this is assessed by determining the PARP levels of cracking
The apoptosis-induced ability of invention compound.
By 1 × 107Individual AMO-1 cells subcutaneous transplantation is into immunosuppressive mouse (SCID strains).12-14 days after transplanting,
Animal is treated by intravenous or oral route with various compounds.After treatment, reclaim and crack tumor mass, in tumor lysis
The PARP of cracking form is quantitative determined in thing.
Quantitative determined using " Meso Scale Discovery (MSD) ELISA platforms " experiment, the experiment can be special
Opposite sex measure PARP cracking form.It is expressed in the form of activity factor, corresponding to the PARP cracked in treatment mouse amount
Divided by the ratio between the PARP cracked in control mice amount.
As a result (show) and show in table 2 below, the compounds of this invention can induce withering for AMO-1 tumour cells in vivo
Die.
Table 2：The quantitative test of internal PARP cracking form
Embodiment D：Internal antitumor activity
The antitumor activity of the compounds of this invention is assessed in the heteroplastic transplantation model of AMO-1 multiple myeloma cells.
By 1 × 107Individual AMO-1 cells subcutaneous transplantation is into immunosuppressive mouse (SCID strains).
6-8 days after transplanting, when tumor mass reaches about 150mm3When, with daily therapeutic scheme (treating for 5 days) using various
Compounds for treating mouse.Tumor mass is measured twice a week since treatment.
The compounds of this invention has antitumor activity (tumor regression) in AMO-1 multiple myeloma models, has Δ
(qualitative parameter of Product Activity, it is determined as follows T/C：Last treatment is subtracted from the median tumor volume on the initial treatment same day to work as
The gross tumor volume for not treating control group on it the median tumor volume/last time treatment same day) scope from -1.5 to -
24.5%.The result of acquisition shows that the compounds of this invention can induce significant tumor regression during treatment.
Embodiment E：Pharmaceutical composition：Tablet
1000 tablets contain the compound 5g selected from embodiment 1-274 that dosage is 5mg
Claims (41)
- Formula 1. (I) compound：Wherein：◆ A represents groupWherein 1 is connected with-NH- groups, and 2 are connected with aromatic ring,◆ E representation ring alkyls, Heterocyclylalkyl, aryl or heteroaryl,◆ X represents nitrogen-atoms or C-R4Group,◆ Y represents nitrogen-atoms or C-R3Group,◆R1Represent halogen atom, straight or branched (C1-C6) alkyl, straight or branched (C2-C6) alkenyl, straight or branched (C2-C6) alkynyl, straight or branched (C1-C6) multi-haloalkyl, hydroxyl, hydroxyl (C1-C6) alkyl, straight or branched (C1-C6) alkane Epoxide ,-S- (C1-C6) alkyl, cyano group, nitro ,-alkyl (C0-C6)-NR9R9' ,-O- alkyl (C1-C6)-NR9R9' ,-O- alkyl (C1-C6)-R10、-C(O)-OR9、-O-C(O)-R9、-C(O)-NR9R9’、-NR9-C(O)-R9’、-NR9-C(O)-OR9' ,-alkyl (C1-C6)-NR9-C(O)-R9’、-SO2-NR9R9’、-SO2- alkyl (C1-C6),◆R2、R3、R4And R5Hydrogen atom, halogen atom, straight or branched (C are independently represented each other1-C6) alkyl, straight chain or Side chain (C2-C6) alkenyl, straight or branched (C2-C6) alkynyl, straight or branched (C1-C6) multi-haloalkyl, hydroxyl, hydroxyl (C1-C6) alkyl, straight or branched (C1-C6) alkoxy ,-S- (C1-C6) alkyl, cyano group, nitro ,-alkyl (C0-C6)- NR9R9' ,-O- alkyl (C1-C6)-NR9R9' ,-O- alkyl (C1-C6)-R10、-C(O)-OR9、-O-C(O)-R9、-C(O)- NR9R9’、-NR9-C(O)-R9’、-NR9-C(O)-OR9' ,-alkyl (C1-C6)-NR9-C(O)-R9’、-SO2-NR9R9' or-SO2- alkane Base (C1-C6),Or a pair of (R1、R2) substituent form the aromatics being made up of 5-7 ring memberses together with the carbon atom for carrying them Or non-aromatic ring, it can contain the 1-3 hetero atoms for being selected from oxygen, sulphur and nitrogen, it will be appreciated that the ring formed can be by 1- 2 substitute selected from following group：Halogen, straight or branched (C1-C6) alkyl ,-alkyl (C0-C6)-NR9R9’、-NR11R11’、- Alkyl (C0-C6)-Cy1Or oxo,◆R6Represent hydrogen atom, halogen atom, straight or branched (C1-C6) alkyl, straight or branched (C2-C6) alkenyl, straight chain Or side chain (C2-C6) alkynyl, straight or branched (C1-C6) multi-haloalkyl, hydroxyl, straight or branched (C1-C6) alkoxy ,-S- (C1-C6) alkyl, cyano group, nitro ,-alkyl (C0-C6)-NR9R9’、-O-Cy1,-alkyl (C0-C6)-Cy1,-alkenyl (C2-C6)- Cy1,-alkynyl (C2-C6)-Cy1,-O- alkyl (C1-C6)-R10、-C(O)-OR9、-O-C(O)-R9、-C(O)-NR9R9’、-NR9-C (O)-R9’、-NR9-C(O)-OR9' ,-alkyl (C1-C6)-NR9-C(O)-R9’、-SO2-NR9R9' or-SO2- alkyl (C1-C6),◆R7Represent hydrogen atom, straight or branched (C1-C8) alkyl ,-CHRaRbGroup, aryl, heteroaryl, aryl alkyl (C1-C6) Group or heteroaryl alkyl (C1-C6) group,◆R8Represent straight or branched (C1-C6) alkyl, straight or branched (C2-C6) alkenyl, straight or branched (C2-C6) alkynes Base ,-Cy2, halogen atom, cyano group ,-C (O)-R11Or-C (O)-NR11R11',◆R9And R9' hydrogen atom, straight or branched (C are independently represented each other1-C6) alkyl,Or a pair of (R9、R9') substituent form the aromatics being made up of 5-7 ring memberses together with the nitrogen-atoms for carrying them Or non-aromatic ring, it can contain the 1-3 hetero atoms for being selected from oxygen, sulphur and nitrogen in addition to nitrogen-atoms, it will be appreciated that the nitrogen Hydrogen atom or straight or branched (C can be represented1-C6) alkyl a group substitution,◆R10Representative-Cy3、-Cy3- alkyl (C0-C6)-Cy4、-C(O)-NR9R9’、-NR9R9’、-OR9、-NR9-C(O)-R9’、-O- Alkyl (C1-C6)-OR9、-SO2-R9、-C(O)-OR9Or-NH-C (O)-NH-R9,◆R11And R11' hydrogen atom or optionally substituted straight or branched (C are independently represented each other1-C6) alkyl,◆R12Represent hydrogen atom, hydroxyl or hydroxyl (C1-C6) alkyl,◆RaRepresent hydrogen atom or straight or branched (C1-C6) alkyl,◆RbRepresentative-O-C (O)-O-RcGroup ,-O-C (O)-NRcRc' group or-O-P (O) (ORc)2Group,◆RcAnd Rc' hydrogen atom, straight or branched (C are independently represented each other1-C8) alkyl, cycloalkyl, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy carbonyl (C1-C6) alkyl,Or a pair of (Rc、Rc') substituent formed together with the nitrogen-atoms for carrying them be made up of 5-7 ring memberses it is non-aromatic Race's ring, it can contain the 1-3 hetero atoms selected from oxygen and nitrogen in addition to nitrogen-atoms, it will be appreciated that the nitrogen can be represented Straight or branched (C1-C6) alkyl a group substitution,◆Cy1、Cy2、Cy3And Cy4Independent representation ring alkyl, Heterocyclylalkyl, aryl or heteroaryl each other,◆ n is the integer equal to 0,1 or 2,It should be understood that：- " aryl " refers to phenyl, naphthyl, xenyl,- " heteroaryl " refers to any single- or double- cyclic group being made up of 5-10 ring memberses, and it has at least one aromatics Part and the hetero atoms selected from oxygen, sulphur and nitrogen containing 1-3,- " cycloalkyl " refers to any single- or double- ring non-aromatic carbocycle group, and it contains 3-10 ring memberses,- " Heterocyclylalkyl " refers to any single- or double- ring non-aromatic carbocycle group, and it contains 3-10 ring memberses and contains 1-3 The individual hetero atom selected from oxygen, sulphur and nitrogen, it can include fusion, bridging or spirocyclic ring system,So defined aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl and alkyl, alkenyl, alkynyl, alkoxy may quilts 1-4 substitute selected from following group：Straight or branched (the C optionally substituted1-C6) alkyl, the straight or branched that optionally substitutes (C2-C6) alkenyl, the straight or branched (C that optionally substitutes2-C6) alkynyl, the straight or branched (C that optionally substitutes1-C6) alcoxyl The base, (C optionally substituted1-C6) alkyl-S-, hydroxyl, hydroxyl (C1-C6) alkyl, oxo (or N- oxides, if appropriate Words), nitro, cyano group ,-C (O)-OR ' ,-O-C (O)-R ' ,-C (O)-NR ' R " ,-O-C (O)-NR ' R " ,-NR ' R " ,-(C= NR’)-OR”、-O-P(O)(OR’)2、-O-P(O)(O-M+)2, straight or branched (C1-C6) multi-haloalkyl, trifluoromethoxy, halogen The aldohexose of element or following formula：Wherein each R ' is independent；It should be appreciated that the R ' and R " independently represents hydrogen atom or optionally substituted straight or branched (C each other1-C6) alkane Base, M+Pharmaceutically useful univalent cation is represented,Their enantiomer, diastereoisomer and atropisomer and its addition salts formed with pharmaceutically useful acid or alkali.
- 2. formula (I) compound of claim 1, wherein：◆R1And R2Halogen atom, straight or branched (C are independently represented each other1-C6) alkyl, hydroxyl, hydroxyl (C1-C6) alkane Base, straight or branched (C1-C6) alkoxy,Or a pair of (R1, R2) substituent form the aromatic ring being made up of 5-7 ring memberses together with the carbon atom for carrying them, It can include 1-3 nitrogen-atoms, it will be appreciated that the ring formed can be substituted by 1-2 selected from following group：Halogen Element, straight or branched (C1-C6) alkyl or-alkyl (C0-C6)-NR9R9',◆R3Represent hydrogen atom, halogen atom, straight or branched (C1-C6) alkyl, hydroxyl, straight or branched (C1-C6) alkoxy Or-O- alkyl (C1-C6)-NR9R9',◆R4And R5Hydrogen atom, halogen atom, straight or branched (C are independently represented each other1-C6) alkyl, hydroxyl, straight chain or branch Chain (C1-C6) alkoxy,◆R6Represent hydrogen atom, halogen atom, straight or branched (C1-C6) alkyl, straight or branched (C1-C6) multi-haloalkyl, Hydroxyl, straight or branched (C1-C6) alkoxy, cyano group, nitro ,-alkyl (C0-C6)-NR9R9' ,-alkyl (C0-C6)-Cy1、-O- Alkyl (C1-C6)-R10Or-C (O)-NR9R9',◆R7Represent hydrogen atom, straight or branched (C1-C8) alkyl ,-CHRaRbGroup or heteroaryl alkyl (C1-C6) group,◆R8Represent straight or branched (C1-C6) alkyl, straight or branched (C2-C6) alkenyl, straight or branched (C2-C6) alkynes Base ,-Cy2, halogen atom or-C (O)-R11,◆R9And R9' hydrogen atom or straight or branched (C are independently represented each other1-C6) alkyl,Or a pair of (R9, R9') substituent formed together with the nitrogen-atoms for carrying them be made up of 5-7 ring memberses it is non-aromatic Ring, it can contain the 1-3 hetero atoms selected from oxygen and nitrogen in addition to nitrogen-atoms, it will be appreciated that the nitrogen can be represented straight Chain or side chain (C1-C6) alkyl a group substitution,◆R10Representative-Cy3Or-Cy3- alkyl (C0-C6)-Cy4,◆R11Represent straight or branched (C1-C6) alkyl,So defined aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl and alkyl, alkenyl, alkynyl, alkoxy may quilts 1-4 substitute selected from following group：Straight or branched (the C optionally substituted1-C6) alkyl, the straight or branched that optionally substitutes (C1-C6) alkoxy, hydroxyl, oxo (or N- oxides, if appropriate) ,-C (O)-OR ' ,-C (O)-NR ' R " ,-O-C (O)-NR’R”、-NR’R”、-O-P(O)(OR’)2、-O-P(O)(O-M+)2, straight or branched (C1-C6) multi-haloalkyl, halogen Or the aldohexose of following formula：Wherein each R ' is independent；It should be appreciated that the R ' and R ' ' independently represent hydrogen atom or optionally substituted each other Straight or branched (C1-C6) alkyl, M+Represent pharmaceutically useful univalent cation.
- 3. the compound of claim 1, wherein n are the integer equal to 1.
- 4. the compound of claim 1, wherein selected from R2、R3、R4And R5At least one group do not represent hydrogen atom.
- 5. the compound of claim 1, wherein R12Represent hydrogen atom.
- 6. the compound of claim 1, wherein R1Represent straight or branched (C1-C6) alkyl or halogen atom.
- 7. the compound of claim 1, wherein R2Represent straight or branched (C1-C6) alkoxy, hydroxyl or halogen atom.
- 8. the compound of claim 1, wherein X represent C-R4Group.
- 9. the compound of claim 1, wherein Y represent C-R3Group.
- 10. the compound of claim 1, wherein R4And R5Represent hydrogen atom.
- 11. the compound of claim 1, one pair of which (R1,R5) substituent be identical, a pair of (R2,R4) substituent be Identical.
- 12. the compound of claim 1, wherein：RepresentWherein R1、R2、R9And R9' as defined in claim 1.
- 13. the compound of claim 1, wherein：RepresentWherein R9And R9' as defined in claim 1.
- 14. the compound of claim 1, wherein E represent phenyl, pyridine -2- bases, cyclohexyl, pyrazol-1-yl, cyclopenta, Yin Diindyl -4- bases, cyclopropyl, pyridin-3-yl, indol-3-yl, naphthalene -1- bases, imidazol-4 yl or pyridin-4-yl.
- 15. the compound of claim 1, it is formula (I-b) compound：Wherein R1、R2、R5、R6、R7、R12, X, Y, A and n such as formula (I) defined.
- 16. the compound of claim 1, wherein R6Represent hydrogen atom；Fluorine atom；Chlorine atom；Bromine atoms；Methyl；Trifluoromethyl； Hydroxyl；Methoxyl group；Linearly (C1-C6) alkoxy, it is substituted by halogen atom ,-C (O)-NR ' R " groups or-NR ' R " groups；Cyanogen Base；Nitro；Amino methyl；Benzyl；- O- alkyl (C1-C6)-R10；-C(O)-NR9R9’。
- 17. the compound of claim 1, wherein R7Represent hydrogen atom, optionally substituted straight or branched (C1-C6) alkyl ,- CHRaRbGroup or heteroaryl alkyl (C1-C6) group.
- 18. the compound of claim 1, wherein R8Represent straight or branched (C2-C6) alkynyl, aryl or heteroaryl.
- 19. the compound of claim 1, wherein R9And R9' straight or branched (C is independently represented each other1-C6) alkyl, or A pair of (R9,R9') substituent the non-aromatic ring of 5-7 ring members composition is formed together with the nitrogen-atoms for carrying them, it is removed The 1-3 hetero atoms selected from oxygen and nitrogen can be contained outside nitrogen-atoms, it will be appreciated that the nitrogen can be by straight or branched (C1-C6) alkyl substitution.
- 20. the compound of claim 1, wherein R10Representative-Cy3Or-Cy3- alkyl (C0-C6)-Cy4。
- 21. the compound of claim 20, wherein Cy3Representation ring alkyl, aryl or heteroaryl.
- 22. the compound of claim 20, wherein Cy4Represent phenyl or morpholinyl.
- 23. the compound of claim 20, wherein：R10RepresentWherein p be 0 or 1 integer, R15Represent hydrogen atom, hydroxyl, optionally substituted straight or branched (C1-C6) alkyl, straight chain Or side chain (C1-C6) alkoxy ,-O- (CHR16-CHR17-O)q- R ' group ,-O-P (O) (OR ')2Group ,-O-P (O) (O-M+)2 Group ,-O-C (O)-NR18R19Group, two (C1-C6) alkyl amino (C1-C6) alkoxy, halogen atom or following formula aldohexose：Wherein each R ' is independent；It should be understood that：◆ R ' represents hydrogen atom or straight or branched (C1-C6) alkyl,◆R16Represent hydrogen atom or (C1-C6) alkoxy (C1-C6) alkyl,◆R17Represent hydrogen atom or hydroxyl (C1-C6) alkyl,◆R18Represent hydrogen atom or (C1-C6) alkoxy (C1-C6) alkyl,◆R19Represent (C1-C6) alkoxy (C1-C6) alkyl ,-(CH2)r-NR9R9' group or-(CH2)r-O-(CHR16-CHR17- O)q- R ' group,◆ q 1,2 or 3 integer, r are 0 or 1 integer,◆M+Represent pharmaceutically useful univalent cation.
- 24. the compound of claim 23, wherein the aldohexose is D-MANNOSE.
- 25. the compound of claim 1, the compound are：- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorophenyls) thiophene And [2,3-d] pyrimidine-4-yl] -2- [(1- methyl isophthalic acid H- pyrazoles -5- bases) methoxyl group]-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorophenyls) thiophene And [2,3-d] pyrimidine-4-yl] -2- [(2- ethyoxyls pyrimidine-4-yl) methoxyl group]-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorophenyls) thiophene And [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (furans -2- bases) thiophene And [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- (2,2,2- trifluoro ethoxy)-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- (pyridine -2- ylmethoxies)-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- [(1- methyl isophthalic acid H- pyrazoles -5- bases) methoxyl group]-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- [(1- ethyl -1H- pyrazoles -5- bases) methoxyl group]-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- [(2- ethyoxyls pyrimidine-4-yl) methoxyl group]-D-phenylalanine,- 2- [(1- butyl -1H- pyrazoles -5- bases) methoxyl group]-N- [5- { 3- chloro -2- methyl -4- [2- (4- methyl piperazines -1- Base) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2,2,2- trifluoro ethoxy) pyrimidine-4-yl] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (5- fluorine furans -2- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- methoxyl groups-D-phenylalanine,- 2- [(1- tert-butyl -1H- pyrazoles -5- bases) methoxyl group]-N- [5- 3- chloro -2- methyl -4- [2- (4- methyl piperazines - 1- yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1- bases) thieno [2,3-d] pyrimidine-4-yl]-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxy ethyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- { [1- (2,2,2- trifluoroethyls) -1H- pyrazoles -5- bases] methoxyl group }-D- phenylpropyl alcohol ammonia Acid,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (morpholine -4- bases) pyrimidine-4-yl] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2,2,2- trifluoro ethoxy) pyrimidine-4-yl] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes -1- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (propyl- 1- alkynes -1- bases) thienos [2,3-d] pyrimidine-4-yl] -2- { [1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- bases] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (propyl- 1- alkynes -1- bases) thienos [2,3-d] pyrimidine-4-yl] -2- { [2- (morpholine -4- bases) pyrimidine-4-yl] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (propyl- 1- alkynes -1- bases) thienos [2,3-d] pyrimidine-4-yl] -2- { [2- (2,2,2- trifluoro ethoxy) pyrimidine-4-yl] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (propyl- 1- alkynes -1- bases) thienos [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine,- N- [5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (4- fluorophenyls) thieno [2, 3-d] pyrimidine-4-yl] -2- ({ 2- [2- (2- methoxy ethoxies) phenyl] pyrimidine-4-yl } methoxyl group)-D-phenylalanine；-N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorophenyls) Thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine ethyl ester；-N-[(5Sa) -5- { 3- chloro -2- methyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (propyl- 1- alkynes - 1- yls) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine Ethyl ester；-N-[(5Sa) -5- { 3- chloros -4- [2- (dimethylamino) ethyoxyl] -2- aminomethyl phenyls } -6- (propyl- 1- alkynes -1- bases) Thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine ethyl Ester；- N- [5- { 3,5- dichloro- -2,6- dimethyl -4- [2- (4- methylpiperazine-1-yls) ethyoxyl] phenyl } -6- (4- fluorobenzene Base) thieno [2,3-d] pyrimidine-4-yl] -2- { [2- (2- methoxyphenyls) pyrimidine-4-yl] methoxyl group }-D-phenylalanine.
- 26. the preparation method of formula (I) compound of claim 1, it is characterised in that using formula (II-a) compound as raw material：Wherein Z represents bromine or iodine, and A such as formulas (I) are defined, wherein 1 is connected with chlorine atom, 2 are connected with Z group,So that formula (II-a) compound is coupled with formula (III) compound：Wherein R6、R12, E and n such as formulas (I) defined, Alk represents straight or branched (C1-C6) alkyl,Acquisition formula (IV) compound：Wherein R6、R12, A, E and n such as formula (I) defined, Z and Alk as defined hereinabove,So that formula (IV) compound is further coupled with formula (V) compound：Wherein R1、R2、R5, X and Y such as formulas (I) defined, RB1And RB2Represent hydrogen atom, straight or branched (C1-C6) alkyl, or RB1And RB2The ring optionally to methylate is formed together with the oxygen for carrying them,Acquisition formula (VI) compound：Wherein R1、R2、R5、R6、R12, X, Y, A, E and n such as formula (I) defined, Alk for as defined hereinabove,Alk-O-C (O) the -ester functional group of formula (VI) compound is hydrolyzed, obtains carboxylic acid, its can optionally with formula R7'-OH alcohol Or formula R7'-Cl chlorinated compound reaction, wherein R7' represent straight or branched (C1-C8) alkyl ,-CHRaRbIt is group, aryl, miscellaneous Aryl, aryl alkyl (C1-C6) group or heteroaryl alkyl (C1-C6) group, RaAnd RbAs formula (I) defines,Acquisition formula (I) compound, it can be purified according to conventional isolation techniques, if it is desired, be translated into itself and medicine The addition salts of acceptable acid or alkali, are optionally separated into its isomers according to conventional isolation techniques on,It should be appreciated that during the above method be considered as it is appropriate whenever, intitation reagents or synthetic mesophase Some groups (hydroxyl, amino ...) of body can be protected, then deprotection and functionalization, depending on the requirement of synthesis.
- 27. the preparation method of formula (I) compound of claim 1, it is characterised in that using formula (II-b) compound as raw material：Wherein A such as formulas (I) are defined, wherein 1 is connected with chlorine atom, 2 are connected with iodine atom,So that formula (II-b) compound is coupled with formula (V) compound：Wherein R1、R2、R5, X and Y such as formulas (I) defined, RB1And RB2Represent hydrogen atom, straight or branched (C1-C6) alkyl, or RB1 And RB2The ring optionally to methylate is formed together with the oxygen for carrying them,Acquisition formula (VII) compound：Wherein R1、R2、R5, A, X and Y such as formula (I) defined,So that formula (VII) compound is further coupled with formula (III) compound：Wherein R6、R12, E and n such as formulas (I) defined, Alk represents straight or branched (C1-C6) alkyl,Acquisition formula (VI) compound：Wherein R1、R2、R5、R6、R12, X, Y, A, E and n such as formula (I) defined, Alk for as defined hereinabove,Alk-O-C (O) the -ester functional group of formula (VI) compound is hydrolyzed, obtains carboxylic acid, its can optionally with formula R7'-OH alcohol Or formula R7'-Cl chlorinated compound reaction, wherein R7' represent straight or branched (C1-C8) alkyl ,-CHRaRbIt is group, aryl, miscellaneous Aryl, aryl alkyl (C1-C6) group or heteroaryl alkyl (C1-C6) group, RaAnd RbAs formula (I) defines,Acquisition formula (I) compound, it can be purified according to conventional isolation techniques, if it is desired, be translated into itself and medicine The addition salts of acceptable acid or alkali, are optionally separated into its isomers according to conventional isolation techniques on,It should be appreciated that during the above method be considered as it is appropriate whenever, intitation reagents or synthetic mesophase Some groups (hydroxyl, amino ...) of body can be protected, then deprotection and functionalization, depending on the requirement of synthesis.
- 28. Pharmaceutical composition, the Pharmaceutical composition include in claim 1- any one of 25 formula (I) compound or its with can Medicinal acid or the addition salts of alkali and the pharmaceutically useful excipient of one or more in combination.
- 29. the Pharmaceutical composition of claim 28, as antiapoptotic drug.
- 30. the Pharmaceutical composition of claim 29, for treating cancer and autoimmunity and disease of immune system.
- It is white for treating carcinoma of urinary bladder, the cancer of the brain, breast cancer and uterine cancer, chronic lymphatic sample 31. the Pharmaceutical composition of claim 30 Blood disease, colon cancer, the cancer of the esophagus and liver cancer, Iymphoblastic leukemia, acute myeloid leukaemia, lymthoma, melanoma, pernicious blood Liquid disease, myeloma, oophoroma, non-small cell lung cancer, prostate cancer, cancer of pancreas and ED-SCLC.
- 32. purposes of the Pharmaceutical composition of claim 28 in the medicine as anti-apoptotic agent is produced.
- 33. the Pharmaceutical composition of claim 28 is used for treating cancer and the medicine of autoimmunity and disease of immune system in production Purposes in thing.
- 34. purposes of the Pharmaceutical composition of claim 28 in medicine is produced, the medicine is used to treat following disease：Bladder Cancer, the cancer of the brain, breast cancer and uterine cancer, chronic lymphoid leukemia, colon cancer, the cancer of the esophagus and liver cancer, Iymphoblastic leukemia, Acute myeloid leukaemia, lymthoma, melanoma, malignant hematologic disease, myeloma, oophoroma, non-small cell lung cancer, prostate cancer, Cancer of pancreas and ED-SCLC.
- 35. any one of claim 1-25 formula (I) compound or itself and pharmaceutically useful acid or the addition salts of alkali, for controlling Treat carcinoma of urinary bladder, the cancer of the brain, breast cancer and uterine cancer, chronic lymphoid leukemia, colon cancer, the cancer of the esophagus and liver cancer, lymphoblast It is leukaemia, acute myeloid leukaemia, lymthoma, melanoma, malignant hematologic disease, myeloma, oophoroma, non-small cell lung cancer, preceding Row gland cancer, cancer of pancreas and ED-SCLC.
- 36. any one of claim 1-25 formula (I) compound or its with it is pharmaceutically useful acid or alkali addition salts production medicine Purposes in thing, the medicine are used to treat following disease：Carcinoma of urinary bladder, the cancer of the brain, breast cancer and uterine cancer, the white blood of chronic lymphatic sample Disease, colon cancer, the cancer of the esophagus and liver cancer, Iymphoblastic leukemia, acute myeloid leukaemia, lymthoma, melanoma, hematologic Disease, myeloma, oophoroma, non-small cell lung cancer, prostate cancer, cancer of pancreas and ED-SCLC.
- 37. any one of claim 1-25 formula (I) compound and the combination product of cancer therapy drug, the cancer therapy drug choosing From genotoxic drugs, mitotic poison, antimetabolite, proteasome inhibitor, kinase inhibitor and antibody.
- 38. Pharmaceutical composition, the Pharmaceutical composition includes combination and one or more pharmaceutically useful excipient of claim 37.
- 39. the combination product of claim 37, for treating cancer.
- 40. purposes of the combination product of claim 37 in the medicine for treating cancer is produced.
- 41. any one of claim 1-25 formula (I) compound, the cancer of radiotherapy is needed for treating.
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| FR1555747 | 2015-06-23 | ||
| FR1555747A FR3037956B1 (en) | 2015-06-23 | 2015-06-23 | NOVEL AMINO ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
| PCT/EP2016/064436 WO2016207226A1 (en) | 2015-06-23 | 2016-06-22 | New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them |
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